PHYSIOLOGICAL REVIEWS
Vol. 79, No. 1, January 1999
Printed in U.S.A.
Induction of Immunologic Tolerance for Transplantation
ALDO A. ROSSINI, DALE L. GREINER, AND JOHN P. MORDES
Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts
I. Introduction
A. Overview: from the miraculous to Medawar and Merrill
B. The modern era of transplantation
C. Beyond immunosuppression
II. Transplantation Immunology
A. Transplantation terminology
B. Immune response to foreign tissues
C. Host immune responses to allografts
D. Host immune responses to xenografts
E. Mechanisms of graft destruction
III. Immunologic Tolerance
A. New approaches to transplantation
B. Definition of tolerance
C. Genesis of the concept of transplantation tolerance
D. Graft-based tolerance induction
E. Host response-based tolerance induction
IV. Methods to Induce Transplantation Tolerance In Vivo
A. Methods successful in rodents
B. Methods successful in large animals and primates
C. Evidence of tolerance induction in humans
V. Contemporary Clinical Organ Transplantation
A. Criteria for successful transplantation program
B. Issues of graft placement
C. Immunosuppression
VI. Transplantation After Tolerance
A. Demand for transplantation services
B. Potential pitfalls
C. Issues of donor tissue and organ availability
D. Special case of xenografts
E. Conclusion
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Rossini, Aldo A., Dale L. Greiner, and John P. Mordes. Induction of Immunologic Tolerance for Transplantation.
Physiol. Rev. 79: 99–141, 1999.—In the second half of the 20th century, the transplantation of replacement organs
and tissues to cure disease has become a clinical reality. Success has been achieved as a direct result of progress
in understanding the cellular and molecular biology of the immune system. This understanding has led to the
development of immunosuppressive pharmaceuticals that are part of nearly every transplantation procedure. All
such drugs are toxic to some degree, however, and their chronic use, mandatory in transplantation, predisposes
the patient to the development of infection and cancer. In addition, many of them may have deleterious long-term
effects on the function of grafts. New immunosuppressive agents are constantly under development, but organ
transplantation remains a therapy that requires patients to choose between the risks of their primary illness and
its treatment on the one hand, and the risks of life-long systemic immunosuppression on the other. Alternatives to
immunosuppression include modulation of donor grafts to reduce immunogenicity, removal of passenger leukocytes,
transplantation into immunologically privileged sites like the testis or thymus, encapsulation of tissue, and the
induction of a state of immunologic tolerance. It is the last of these alternatives that has, perhaps, the most promise
and most generic applicability as a future therapy. Recent reports documenting long-term graft survival in the
absence of immunosuppression suggest that tolerance-based therapies may soon become a clinical reality. Of
particular interest to our laboratory are transplantation strategies that focus on the induction of donor-specific Tcell unresponsiveness. The basic biology, protocols, experimental outcomes, and clinical implications of tolerancebased transplantation are the focus of this review.
0031-9333/99 $15.00 Copyright q 1999 the American Physiological Society
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I. INTRODUCTION
A. Overview: From the Miraculous to Medawar and
Merrill
1. Cosmas and Damian
rejected a graft from the same donor, or of a first graft in
a recipient that had been preimmunized with material
from the same donor. 6) The closer the ‘‘blood relationship’’ between donor and recipient, the more likely is graft
success.
4. Transplantation genetics and immunosuppression
Human history is replete with chimeras, from
sphinxes to mermaids, and one wonders if the ancients
might actually have dreamed of what we now call xenotransplantation. Certainly they must have dreamed of replacing limbs and other body parts lost to trauma. The
first recorded expression of that dream appears in the
third century legend of Saints Cosmas and Damian (173,
371). The story is told that these physician brothers used
the limb of a Moor who had died to replace the cancerous
leg of a church sacristan. Paintings by Fra Angelico and
others have immortalized the miraculous legend of the
saints’ patient who walked about with one white and one
black leg.1
2. The first successful transplant
There is remarkable evidence that successful transplantation surgery was actually performed by ancient
Hindu vaidya, perhaps 2,000 years ago (236a). The Ayurvedic physicians, among them the author Sushruta, reconstructed noses using pedicle flap grafts from the patient’s own forehead (236a). By 1597, the physician
Gaspare Tagliacozzi was performing similar reconstructive rhinoplasty using skin flaps from the patient’s
arm (371). There were no reports of success using skin
from another person, however (236a, 371). Transplantation progressed little until the 20th century.
3. Laws of transplantation
By the beginning of the 20th century, advances in
surgery, asepsis, and anesthesia had revivified the ancient
dreams of Cosmas and Damian. Animal and some human
transplantation experiments began to be performed.
These suggested that the serious barriers to successful
transplantation would not be technical, but biological.
George Schöne summarized these insights in 1912. He
defined classic ‘‘laws of transplantation’’ that, in the absence of immune intervention, still apply today (371).
These are as follows. 1) Transplantation into a foreign
species invariably fails. 2) Transplantation into unrelated
members of the same species usually fails. 3) Autografts
almost invariably succeed. 4) There is a primary take and
then delayed rejection of the first graft into an unrelated
member of the same species. 5) There is accelerated rejection of a second graft in a recipient that had previously
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Fra Angelico (1387–1455): Dream of the Deacon Justinian, Museo di San Marco, Florence, Italy.
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It was decades more before the basis for these empirical laws was found in studies of the small but prolific
mouse. Clarence C. Little and George Snell (who later won
a Noble prize for this work) had the inspiration to develop
and analyze ‘‘congenic’’ strains of mice. Congenic strains
are genetically identical except at a single chromosomal
locus. By constant breeding and testing for allograft acceptance, Little and Snell pioneered the analysis of what came
to be called the major histocompatibility complex (MHC),
a genetic locus designated H-2 in mice (371). The MHC is
the molecular embodiment of ‘‘blood relationship.’’
Armed with genetic insight, Sir Peter Medawar attempted to apply this information to aid World War II
burn victims who could be helped by skin grafts. Like
Schöne, he observed that 1) autografts succeed, 2) allografts fail after an initial take, and 3) a second allograft
from the same donor undergoes accelerated rejection. He
suggested that ‘‘destruction of the foreign epidermis was
brought about by a mechanism of active immunization’’
(371). As Medawar continued his analyses using rabbits,
his insights led to the recognition that immunosuppression might overcome the laws of transplantation. The development of immunosuppressive agents like nitrogen
mustard and corticosteroids and their evaluation in animal models soon led to the practical application of transplantation as a medical therapy.
In 1954, Merrill, Murray, and Harrison performed the
first successful human vascular organ graft, a kidney
transplant (253). The donor and recipient were monozygotic twins in this ‘‘proof-of-principle’’ intervention, with
genetic identity obviating the need for immunosuppression. The graft survived until the death of the patient 7 yr
later of heart disease. With the advent of an effective
immunosuppressive regimen, the same group went on in
1959 to perform the first kidney graft between unrelated
individuals; that graft survived for 20 yr (252).
B. The Modern Era of Transplantation
The modern era of transplantation has also benefited
from improved therapeutics for those awaiting transplantation, making them better surgical candidates, improved methods of donor organ preservation, and broadening societal awareness of the need for organ donation.
Above all, however, the key to successful transplantation has been the discovery and improvement of strategies
for immunosuppression. Radiation of the host came first,
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but was rapidly supplanted by immunosuppressive drugs
including glucocorticoids, azathioprine, and antilymphocyte serum. Newer immunosuppressive drugs with greater
potency and wider margins of safety have improved the
outcome of renal allografts and generated the first consistent success with cardiac, liver, lung, and pancreas grafts
(138). The first of these second-generation drugs was
cyclosporine. Newer agents include tacrolimus (formerly
called FK-506), monoclonal antibodies like anti-CD3, and
many other biologic (393) and nonbiologic agents (262).
C. Beyond Immunosuppression
The success achieved by solid organ transplant surgeons since the pioneering work of the 1950s has been
extraordinary. More than 90% of living related donor and
80–85% of cadaveric kidney grafts are now functional
after 1 yr (279, 294). Comparable success has been
achieved in the areas of heart, lung, liver, and to a lesser
extent pancreas transplantation. This success, however,
belies some important residual problems.
At this time, all successful treatment of human disease by transplantation (other than between monozygotic
siblings) requires the use of general immunosuppressive
agents (138). All such drugs are toxic to some degree, and
toxicity often leads to patient noncompliance. The drugs
are also known to predispose to both infection and neoplasia. Some 10–45% of persons who are chronically immunosuppressed after transplantation develop a neoplasm after 10 yr, and 40–75% do so after 20 yr (75, 272).
In addition, many immunosuppressive drugs have deleterious long-term effects on the function of transplanted
organs (138), e.g., b-cells in the case of transplantation
for diabetes and cyclosporine-induced nephrotoxicity in
cardiac and liver transplant recipients (410). New immunosuppressive agents are constantly under development
(262, 393), but transplantation of any organ or tissue into
an unrelated human currently requires patients to accept
the risks of life-long systemic immunosuppression.
Another critical problem is that of ‘‘chronic rejection.’’ Although the majority of renal grafts are functional
at 1 yr, only 20% will be functional at 10 yr (294). The
pathology and mechanisms of this indolent form of graft
failure are only beginning to be understood (15, 145, 146,
298).
A final issue is recurrence of disease in a successfully
transplanted organ. Recurrence may take the form of atherosclerosis in a cardiac allograft or recurrence of tissuespecific disease processes, for example, recurrent autoimmune destruction of pancreatic islets or recurrent lupus
nephritis.
Finding alternatives to immunosuppression that will
prevent both immediate and long-term graft rejection will
require further understanding of the mechanisms by
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which Schöne’s six laws operate. Immunosuppression is
based on interference with the immune system. Understanding immunologic processes better may allow us to
redirect the immune response to favor graft acceptance.
We next review our current understanding of transplantation immunobiology and newer approaches to transplantation. These include modulation of transplant immunogenicity (sects. IIID1 and IIID2), removal of passenger
leukocytes (sect. IVA7), transplantation into immunologically privileged sites like the testis or thymus (sect. IIID3),
mechanical encapsulation of tissues (199), and the induction of a state of immunologic tolerance. It is the last
of these alternatives that has, perhaps, the most generic
promise of revolutionizing tissue transplantation. Induction of transplantation tolerance is the focus of work in
our laboratory and the primary focus of this review.
II. TRANSPLANTATION IMMUNOLOGY
A. Transplantation Terminology
Transplauten is a Middle English agricultural word
used literally to describe the removal of a plant from one
place to another. Its modern surgical adaptation refers to
the transfer of an organ or tissue from one part of the
body to another or from one individual, the donor, to
another, the recipient. If donor and recipient are the same
individual, a graft is autologous. If donor and recipient
are monozygotic, a graft is syngeneic. If donor and recipient are any other same-species individuals, a graft is allogeneic. If the donor and recipient are of different species,
a graft is xenogeneic (174).
Orthotopic grafts are placed in the normal anatomic
location of that organ; heterotopic grafts are located in
other sites of convenience, e.g., intrahepatic placement of
pancreatic islets. If a graft heals and functions, it is accepted; if destroyed by the immune system, it is rejected.
Rejection may be hyperacute (within minutes to hours)
or acute (usually within the first month after grafting).
Rejection can also be chronic, with slow, gradual destruction over months to years. If the immune system has not
previously been sensitized to the donor’s tissues, the rejection is termed a first-set rejection. In presensitized recipients, the rejection is a second-set rejection.
B. Immune Response to Foreign Tissues
Many processes participate in the response to all foreign tissue grafts. These include the local inflammatory
response to surgery, the processes that initiate wound
repair and vascular endothelialization, and the immune
response to the recognition of nonself antigen. The basic
elements of this response are schematized in Figure 1.
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FIG. 1. Overview of host immune response to foreign tissue. Host immune response is mediated by mononuclear cells
composed of CD4/ and CD8/ T cells (T),
macrophages (Mf), natural killer cells
(NK), and B cells (B). CD8/ T cells interact with major histocompatibility complex (MHC) class I plus peptide present
on graft, including its endothelial cells;
CD4/ T cells interact with MHC class II
plus peptide present on both graft and
endothelial cells. Endothelial cells are depicted as activated in response to inflammatory cytokines, expressing surface molecules that include both MHC
molecules and adhesion molecules. Bottom depicts mechanisms of graft destruction associated with various responding
host immune cells. Finally, also depicted
is possibility of deviation of immune response by Th2-type cytokines produced
by CD4/ T cells. ADCC, antibody-dependent cell-mediated cytotoxicity.
The response to nonself antigen involves both cellular and humoral immunity. The goal of the response is
to reject that antigen, and its nature and intensity are
determined by two factors. The first is the biology of the
foreign tissue, whether it is an allograft or a xenograft, a
vascularized organ or dispersed tissue, a fresh tissue or
one that has been pretreated to reduce antigenicity. The
second factor is the host response to the encounter with
that specific foreign tissue. These responses fall into three
categories: hyperacute, acute, and chronic rejection.
1. Hyperacute rejection of discordant xenografts
‘‘Natural antibodies’’ in human recipients cause hyperacute rejection of ‘‘discordant’’ vascularized xenografts
(67, 109, 328, 426). These predominantly IgM antibodies
recognize a-galactosyl residues that are absent on human
(and all old-world primate) endothelial cells but present
on endothelium in many other species. They bind to xenogeneic endothelium and fix complement, leading to vascular leakage and thrombosis. The process can cause xenograft rejection in minutes to hours. Preformed anti-a-galactosyl natural antibodies are a major obstacle to the
transplantation, for example, of porcine xenografts into
humans (128, 149). In contrast, transplantation of allografts never encounters the obstacle of hyperacute rejection due to anti-a-galactosyl natural antibodies. Hyperacute rejection is, however, a well-recognized risk in the
case of allografts transplanted into sensitized recipients
who have preformed antibodies against allogeneic human
leukocyte antigens (HLA). Anti-HLA antibodies occur in
individuals exposed to non-self HLA antigens by blood
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transfusion, pregnancy, prior transplantation, or bacterial
infections that induce cross-reacting antibodies to HLA
epitopes (170).
Based on the presence or absence of a-galactosyl
residues or anti-a-galactosyl natural antibodies, xenografts can be classified into two groups (11, 343). Concordant xenografts do not elicit hyperacute humoral rejection
responses. This occurs most often when donor and recipient are members of closely related species (e.g., rat and
mouse). Discordant xenografts do elicit hyperacute rejection responses and commonly occur when donor and recipient are members of less-related species.
Strategies for overcoming hyperacute rejection include genetic engineering of xenograft donors to express
human complement inhibitors like CD46, CD55, and CD59
(67, 280, 338) or to knock out genes required for the expression of a-galactosyl residues (228, 441). Another approach is prophylactic pretreatment of the human xenograft recipient, for example, by plasmapheresis to remove
natural antibodies or by injection of soluble inhibitors of
complement such as CD35 (110, 228). Other proposed
therapies address events downstream of natural antibody
binding and include the administration of antioxidant
drugs to maintain the platelet-inhibiting enzyme ecto-ATPase in its active form (67, 280, 338) and depletion of complement by cobra venom. Because none of these promising strategies for overcoming hyperacute rejection involves the induction of tolerance, they are not discussed
further.
2. Acute rejection
In the absence of a hyperacute rejection response,
all transplanted tissues, except for those from identical
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siblings, engender an acute rejection response. This response is based on the recognition of the foreign tissue
as nonself. The basis for recognition of self resides with
a system of cell-surface glycoproteins.
All living tissues express families of cell-surface proteins that comprise the MHC. For historical reasons, MHC
proteins are given the prefix H2 in mice, RT1 in rats, and
HLA in people. Alleles of MHC proteins are extremely
polymorphic, and chance MHC identity between individuals other than monozygotic siblings is extremely rare.
When an allograft is transplanted, the disparity in MHC,
or ‘‘alloantigenicity,’’ constitutes recognition of nonself
and incites a number of reactions.
The interaction of graft alloantigens with the host
immune system leads to the activation of several classes
of cells. In the first stages of transplantation, as the organ
becomes vascularized, there is rapid infiltration of host
immune cells into the graft. The infiltrate is composed
mostly of mononuclear cells. Although the exact composition of the infiltrate over time is not precisely known, it
is presumed that those host mononuclear cells with the
capacity to present nonself antigens to the host predominate. Details of this process are presented in section IIC2.
3. Chronic rejection
The third major form of graft rejection occurs months
to years after transplantation, even in the presence of
continued immunosuppression. The majority of kidney
transplants, which now have an initial acceptance rate of
ú90%, inevitably fail due to the development of chronic
rejection and loss of function (279, 294). The pathological
hallmark of an organ undergoing chronic rejection is fibrosis, leading to distortion of normal architecture. The
pathology is comparable to that which accompanies
wound healing, and it has been suggested that chronic
rejection is the end result of healing in response to recurring episodes of acute rejection. Other suggested mechanisms include delayed-type hypersensitivity with activation of T-helper cells and B cells (346) leading to activation of macrophages and the secretion of tissue growth
factors. Another possibility is antibody-mediated humoral
rejection (see sect. IIE10) or endothelial cell damage leading to ischemia (1). In addition, nonimmunologic factors,
e.g., ischemia and vascular injury, may contribute to
chronic rejection. These factors include maladaptive responses to prior acute injury. The basis of the development of chronic rejection is unknown, and currently available therapies generally fail to reverse chronic rejection,
eventually leading to graft failure (15, 146, 298).
4. Graft versus host disease
Immune responses to foreign tissue are not totally
unidirectional. Essentially all organ and tissue grafts carry
with them elements of the host immune system. In the
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special case of lymphohemopoietic grafts, the immune
system components of the graft are able to mount an
immune response to the host. This is termed graft versus
host disease (GVHD). In the case of solid organ grafts,
however, GVHD is not a typical complication. Donor immune cells, may, however, persist at low levels in the
recipient, leading to a state of ‘‘microchimerism.’’
5. Microchimerism
It has been suggested that passenger leukocytes present in at least some successful allografts migrate after
organ transplantation and produce persistent chimerism
(385). The level of engraftment is low, but it has been
argued that a microchimeric state may be essential for
sustained survival of allografts (385). The intentional augmentation of microchimerism by cotransplantation of
bone marrow together with an organ graft to induce tolerance (46, 276, 446) is discussed in section III.
C. Host Immune Responses to Allografts
1. Role of the major histocompatibility complex
As noted above, the host MHC plays the defining role
in acceptance or rejection of a graft. The more closely
the donor graft and the host are matched for MHC, the
greater the likelihood of the graft acceptance by the host.
The family of MHC cell-surface proteins is subdivided into
two major subclasses that play pivotal yet different roles
in the determination of self versus nonself by the immune
system. These are designated as the MHC class I and the
MHC class II antigens.
Host T cells can recognize a foreign antigen and generate an immune response, only when foreign antigens
are ‘‘presented’’ to its T-cell receptor (TCR) by an MHC
class I or class II molecule. In most cases, host MHC class
I does not readily present antigens derived from a donor
graft, although a mechanism for this type of antigen presentation has been proposed (69, 331, 453). In general,
MHC class I molecules present self-antigens derived from
intracellular degradation of proteins. These processed antigens are expressed in a cleft present in the extracellular
domain of the MHC molecule. Presentation of foreign donor antigens and activation of host-reactive T cells occurs
through the MHC class II molecule. Antigens taken up by
endocytosis and processed by host antigen presenting
cells (APC) are readily presented to the host immune system by the host MHC class II molecule (69, 331, 453).
In transplantation, this is primarily the presentation of
alloantigen or xenoantigen.
In addition to MHC antigens, the immune system can
also respond to so-called minor histocompatibility antigens present on grafts. Response to these antigens is indolent, and graft rejection based solely on these antigens is
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slow (360, 432). An example of a minor histocompatibility
antigen is the male Y antigen (360).
Peptides noncovalently bound to MHC molecules
provide the immune system with antigenic targets. In addition, the presence of peptide bound to MHC molecules
lengthens the life span of those MHC molecules on the
cell surface of the APC (270). Major histocompatibility
complex without peptide has a very short life span and
is rapidly lost from the cell surface. The predominant response of the host immune system to foreign tissue is
not simply to alloantigen but rather to the allo-MHC plus
peptide unit. Direct recognition of allo-MHC without
bound peptide can occur, however, and T-cell clones reactive to allo-MHC in the absence of peptide can mediate
skin allograft rejection (375).
The strategies to induce tolerance described in section IV are directed at altering the acute rejection response. In molecular terms, they are directed at redefining
the MHC plus peptide complexes present on the graft as
‘‘self’’ by reeducating the host immune response.
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and then proliferate. These lymphocytes are found in
lymph nodes draining the graft site as well as in peripheral
blood and spleen. They are directed against graft antigens
presented by either MHC class I or class II molecules on
APC. The net effect is activation of the immune system
and initiation of immune rejection.
Graft destruction can be effected by direct cell-tocell contact between activated effector T cells and the
targeted graft resulting in delivery of a cytotoxic molecule.
Alternatively, graft rejection may be mediated by indirect
mechanisms including lymphokine-induced destruction
(see sect. IIE).
2. Antigen presenting cells
The primary APC in the immune system are dendritic
cells and macrophages. These cells are termed ‘‘professional antigen presenting cells’’ because of their ability to
provide accessory cytokines and costimulatory molecules
needed for initiation of maximal T- and B-lymphocyte immune reactivity. There are many other types of cells that
can present antigen to the immune system, but in general,
these do not provide all of the factors necessary for the
initiation of an immune rejection response. These ‘‘nonprofessional’’ APC include endothelial cells and resting B
lymphocytes.
Macrophages are among the first APC to infiltrate a
graft. They both initiate and mediate the inflammatory
process. Macrophages are able to 1) process and present
the antigen to the immune system, 2) release monokines
that are both chemoattractant and immunostimulatory,
3) release chemokines that are also chemoattractant and
proinflammatory, and 4) scavenge debris from necrotic
graft tissue.
Another class of professional APC, dendritic cells,
can be distinguished from monocytes and macrophages
by cytochemical, physical, and morphological characteristics. Dendritic cells reside in the interstitial space of many
tissues, process and present antigen, interact with and
stimulate T cells, and contribute to allograft rejection. It
is now recognized that the ‘‘passenger leukocytes’’ responsible for the immunogenicity of many grafts are probably
dendritic cells. Treatments that remove or block dendritic
cells have been shown to prolong the survival of transplanted grafts (142) (see sect. IVA7).
4. B lymphocytes
The role of antibodies in graft rejection is controversial. T lymphocytes alone are sufficient for rejection of a
graft. The humoral response to the graft could, however,
participate in this process either by synergizing with T
cells or by antagonizing them so as to impede rejection.
The humoral immune response to a graft generates
antibodies that could synergize with the cellular immune
system to enhance graft rejection in several ways. First,
graft-reactive antibodies may provide an adherence signal
that ‘‘marks’’ a graft and directs macrophages, mononuclear cells, and neutrophils to recognize and attack it.
Second, bound antibodies could initiate antibody-dependent cell-mediated cytotoxicity (ADCC), a process in
which cells like natural killer cells recognize the Fc portion of bound immunoglobulin and, again, attack the
marked graft. Third, antibodies may bind to many target
antigens, form immune complexes, and impair the function of the graft. Immune complexes are also recognized
by macrophages, again enhancing cellular immunity to
the graft. Finally, the antibody could bind complement.
This process generates two effects. The bound complement binds macrophages through their C3 receptors. This
again enhances macrophage targeting of the marked graft.
Another effect is the activation of complement and direct
complement-mediated lysis of the targeted graft.
Alternatively, antibodies to the graft could act to impair rejection. It has been proposed that antibodies can
provide a protective effect termed immunologic enhancement, or simply enhancement (see sect. IIIE3). What determines whether antibodies to grafts facilitate destructive
mechanisms or instead act to protect grafts from cellmediated destruction is not known. However, as detailed
in section IVA6D, this phenomenon has been demonstrated experimentally in islet transplantation. In those
studies, pretreatment of islets with anti-MHC class I antibody extended the survival of human islet xenografts in
mice (94). The extent to which enhancing antibodies of
host origin may contribute to graft survival is not known.
3. T lymphocytes
After presentation of graft antigens by donor or host
APC, host lymphocytes become sensitized and activated,
5. Direct and indirect antigen presentation pathways
In transplantation, activation of the T-cell component
of the immune response by MHC plus peptide can occur
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FIG. 2. Direct and indirect pathways of
antigen presentation. In the direct pathway,
donor peptide is presented to host immune
system by donor-origin antigen presenting
cells (APC) present in graft. It is thought to
be the primary pathway involved in allograft
responses. In the indirect pathway, donor
peptide that is shed into extracellular space
is endocytosed and presented to recipient
immune system by host APC. It is thought to
be the primary pathway involved in xenograft responses. TCR, T-cell receptor.
in two ways. These are termed direct and indirect antigen
presentation (225). These processes are summarized in
Figure 2. In direct antigen presentation, the MHC molecules on or within the graft present donor antigens directly to host T cells (23, 349). In indirect antigen presentation, antigens ‘‘shed’’ by the graft are thought to be presented to the host immune system by host APC (12, 24,
117, 208, 405).
6. Direct recognition pathway
The direct pathway is believed to be of primary importance in the immune response to allografts (42, 207,
349). All allografts contain passenger APC that are transplanted with the tissue. Their removal in most cases is
difficult. These donor-origin APC, like most nucleated
cells, constitutively express MHC class I molecules that
continuously present self-peptides. In addition, they constitutively express coactivation molecules like CD40 and
B7–1/2 (142). Alloantigenic peptides presented by donor
class I MHC molecules appear to be key targets of T-cell
recognition in allorejection (23, 349). T cells of the CD8/
MHC class I-restricted subset directly engage these peptide-MHC class I complexes on APC, receive costimulatory signals, become activated, and undertake to destroy
the target (405).
This process was first demonstrated in thyroid transplantation (192, 193) and appears to play an important
role in islet allograft rejection (68, 95, 190, 372). The case
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of the islet graft is particularly interesting. The passenger
donor-origin leukocytes present in grafted islets are APC
that express both MHC class I and class II antigens. Islet
cells express only class I MHC and no costimulatory molecules on their surface. Removal of passenger leukocytes
from the graft removes APC that express MHC class II
and costimulatory molecules. This leaves islets with only
MHC class I antigen and no costimulatory molecules. This
in turn inhibits the host’s ability to respond to foreign
alloantigen on the donor islets by the direct presentation
pathway, and the graft survives. Several studies support
this concept. In some studies, APC were depleted by culturing islet grafts at 247C or with 95% O2 (189). In others,
grafts were treated with anti-MHC class II antibody to
remove APC. Still others have used a diet low in essential
fatty acids to induce emigration of passenger leukocytes
from donor islets (209). Each of these methods was reportedly effective in preventing allograft rejection, demonstrating clearly the important role of donor-origin APC
present in a graft.
Although direct antigen presentation appears to play
a key role in acute rejection, it is less likely to be important in chronic rejection (42).
7. Indirect recognition pathways
Indirect antigen recognition is based on the theory
that donor graft antigen can be shed, subsequently taken
up by endocytosis by host-origin APC, processed, and
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then presented to the host immune system as a self-MHCplus-foreign peptide unit. In the indirect pathway, host T
cells recognize graft alloantigens presented by a host APC.
This form of antigen presentation by the MHC class II
molecule targets class II-restricted host CD4/ T cells, resulting in their activation in response to the graft. Definitive demonstration of indirect antigen presentation and
its role in transplantation rejection has been difficult, but
convincing evidence has emerged. Indirect allorecognition appears to have a role in chronic allograft rejection
(see sect. IIB3), a phenomenon that is mediated in part
by the activation of T-helper cells and of alloantibodyproducing B cells (42, 346).
The activation of T cells following antigen presentation by the indirect pathway may be less efficient than
that of T cells primed by the direct pathway (346). Furthermore, the T-cell repertoire appears to be restricted
following indirect antigen presentation, suggesting that a
more limited number of antigens may be present by this
pathway (224). The classical mechanism of antigen presentation by the indirect pathway involves the uptake of
exogenous antigen by the host MHC class II molecules on
APC and presentation to CD4/ T cells. It has, however,
been suggested that indirect antigen presentation to CD8/
T cells can occur, possibly permitting both CD4/ and
CD8/ host T cells to be activated by donor grafts in the
absence of direct antigen presentation (25, 181).
Indirect antigen presentation is thought to be the major pathway involved in the host response to xenografts,
the subject to which we turn next.
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191) have proposed the concept of ‘‘indirect’’ antigen recognition leading to immune activation and rejection based
on the interaction of recipient CD4/ T cells with recipient
APC presenting graft xenoantigens. The basis of this preference for indirect recognition in the response to xenografts may stem from the inability of the host CD8/ T-cell
population to recognize and interact with the xenogeneic
class I MHC molecules present on the graft itself.
The generation of cytotoxic T cells and the subsequent release of cytokines and free radicals in the vicinity
of grafted tissue are thought then to lead to cytotoxicity
or apoptosis (see sect.IIE). Studies of cytokine gene expression are consistent with this view. For example, Morris et al. (261), studying xenogeneic porcine proislets in
CBA/H mice, have observed that Th2-like CD4/ T cells
appear to be preferentially activated in the course of rejection.
E. Mechanisms of Graft Destruction
There are several mechanisms available to the immune system of a mammalian host to mediate rejection
of a foreign tissue. This redundancy presents additional
hurdles that must be overcome in the area of transplantation. Grafts can be destroyed either directly by delivery
of a ‘‘lethal hit’’ from cytotoxic cells or indirectly by molecules such as cytokines. Both mechanisms involve a broad
diversity of elements within the cellular arm of the immune response (333).
1. Initiation of the effector response
D. Host Immune Responses to Xenografts
1. Immune rejection of xenografts
The cellular immune response to xenografts is distinct from and less well understood than the cellular immune response to allografts (405). Helper and cytotoxic
T-cell responses to xenoantigens are generally slower and
less intense than are responses to alloantigens (149). The
weaker xenoresponse may result from a relative inability
of T cells from one species to interact with APC from
another (117, 445). Interactions requiring the adhesion of
host immune cells to an organ graft may similarly be
weaker across species (149).
2. Direct presentation of xenoantigens
Studies of xenograft rejection suggest that MHC class
II is the predominant antigenic target of the host immune
response and that MHC class II-restricted CD4/ T cells
are the mediators of graft destruction (180, 238, 421). It
has been suggested, in fact, that xenograft rejection may
use a CD4/, cytotoxic T lymphocyte (CTL)-independent
pathway (117, 149). Lafferty, Gill, and co-workers (48, 117,
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The cell population that appears to be most important
in initiating rejection of allografts is the CD4/ T cell (182).
Mice lacking CD4/ cells fail to reject allografts, whereas
mice lacking CD8/ retain their ability to reject allografts
(182). The ability of CD4-deficient mice to retain grafts
may, however, be strain dependent (241). To a first approximation, it can probably be concluded that CD4/ T
cells can both initiate and mediate allograft rejection,
whereas CD8/ T cells are primarily mediators of graft
destruction. The mechanisms available to the T-cell immune system to mediate rejection are described next.
2. Cytotoxic T lymphocytes
Cytotoxic T lymphocytes are major mediators of allograft rejection. The CTL are classically CD8/ cells that
recognize antigen in the context of MHC class I molecules
and, therefore, are important in allograft rejection where
the graft itself can present alloantigen to the immune system. In addition, however, subsets of CD4/ T cells can
also act as CTL (139).
There are at least two major mechanisms by which
CTL can deliver a lethal hit through direct cell-cell con-
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tact. One is by interaction of Fas ligand (FasL, CD95L) on
the activated CTL with Fas (CD95) expressed on the target
cell (see sect. IIE3). The other is by delivery of cytotoxic
molecules termed granzymes (perforin and other molecules like granzyme B; see sect. IIE6).
There are several key features of CTL-mediated cytotoxicity. These include 1) antigen specificity, 2) a requirement for cell-cell contact for killing, and 3) the ability
of CTL to destroy multiple target cells without injury to
themselves. Cytotoxic T lymphocyte-mediated cytotoxicity occurs in several steps. The first is recognition of the
target and conjugate formation, whereby the CTL binds
to the target cell. This binding event leads to activation
signals in the CTL. The activated CTL then delivers a lethal
hit mediated either by granzymes or through the Fas pathway. After these steps, the CTL is released from its conjugation with the target cell, and the target then undergoes
programmed cell death. Efforts in transplantation to prevent many of these steps have been attempted. The most
recent experiments have targeted the Fas-FasL pathway.
3. Fas and Fas ligand
Fas and FasL (CD95 and CD95L) are members of
the tumor necrosis factor (TNF) family of molecules, and
defects in this pathway have been implicated in defective
apoptosis and autoimmunity in animals. Mice homozygous for the lpr or gld mutations develop lymphadenopathy and suffer from a systemic lupus erythematosus-like
autoimmune disease (268). The lpr defect is due to a mutation in the gene encoding Fas, whereas the gld defect is
due to a mutation in the gene encoding FasL (232, 408,
433). Mice with lpr and gld mutations cannot mediate
cytotoxic activity through the Fas-FasL pathway, and as
a result, they do not reject allografts well. The Fas-FasL
pathway has been implicated in clonal selection and control of lymphocyte activation (257, 267, 374) as well as in
killing mediated by cytotoxic T cells (339).
4. Immunologically privileged sites
It has been known for many years that certain anatomic sites are exceptionally permissive to graft acceptance. Islet allografts, for example, are not rejected even
in the absence of immunosuppression when they are
placed heterotopically in the testis (20, 371). It is now
recognized that several of these ‘‘privileged sites’’ are associated with high levels of FasL expression on cells
within the site (127). The interaction between FasL on
tissues in the site and Fas on responding host T cells leads
to destruction of those responding cells and preservation
of the graft.
5. FasL-mediated bystander killing
An additional role of cytotoxic cells in graft rejection
may stem from their ability to self-regulate. T cells acti-
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vated in response to allogeneic stimuli are able to lyse
bystander host alloantigen-activated T cells in an MHCrestricted manner (377). This process is not dependent
on the perforin pathway but rather on the Fas-FasL pathway of cytotoxicity. Cytotoxic T lymphocyte responses to
foreign tissues may therefore cause collateral damage to
local host Fas-expressing cells (377). The role of bystander-cell killing in graft destruction or in the generation
of collateral damage to host tissues is not yet known.
6. Perforin
Perforin is a cytotoxic molecule released into target
cells by CTL during conjugate formation. The role of perforin in cytotoxicity may be direct, forming holes in the
target cell membrane similar to those produced by the
complement cascade. Alternatively, the role of perforin
may be indirect, by increasing the porosity of the target
cell membrane and thereby enhancing the entry of granzymes. The importance of perforin in transplantation has
been highlighted by the observation that mice genetically
deficient in perforin are deficient in their ability to lyse
allo-specific targets in vitro (162). Cytotoxic CD4/ T cells
can also mediate cytotoxicity via the perforin pathway
(444).
7. Natural killer cells
Natural killer cells (NK cells, sometimes designated
as large granular lymphocytes), like CTL, kill target cells
using perforin, granzymes, and proteoglycans. The NK
cells lyse target cells in an MHC-unrestricted manner using receptors that are not antigen specific. The role of NK
cells in allograft rejection is uncertain. The NK cells by
themselves cannot reject allografts, but they are in the
graft-infiltrating cell population and may contribute to
graft damage.
The NK cells have been implicated in the rejection
of xenografts (219). In the absence of T cells and antigraft
antibody, athymic rats reject hamster heart xenografts.
Depletion of NK cells by injection of anti-asialo GM-1 antiserum delays rejection, suggesting that NK cell-mediated
cytotoxicity can be important in xenograft rejection (219).
8. Macrophages
As outlined in section IIC2, macrophages may play
multiple roles in initiating and propagating the immune
response to grafts. Indirect evidence suggests that they
can also mediate graft rejection, at least for xenografts
(219). This conclusion is based on several observations.
1) Spleens from animals that are rejecting xenografts harbor a high percentage of macrophages. 2) Rejected xenografts are infiltrated predominantly by macrophages. Furthermore, macrophages adoptively transferred to athymic
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recipients produce accelerated rejection of newly transplanted xenografts.
9. Dendritic cells
Dendritic cells are among the most potent APC and
play an important role in both direct and indirect antigen
presentation. Dendritic cells, however, are also known to
express FasL and can kill activated Fas-expressing CD4/
T cells (400). This activity may contribute to the resistance
of a graft to host immune-mediated killing. In addition,
dendritic cells can both activate and suppress the host
immune system as a function of their expression of FasL
or costimulatory molecules (230). The presence or absence of dendritic cells in a graft may be a primary determinant of its acceptance (see sect. IVA7).
10. B lymphocytes
As discussed in section IIC4, B lymphocytes and antibody responses have the potential to play many roles in
graft rejection. This has become a matter of increasing
concern with the recognition that ¢50% of patients on
transplantation waiting lists exhibit a high ‘‘panel-reactive
antibody’’ status (340). These high levels of antibody to
multiple MHC antigens usually result from the blood
transfusions patients receive in the course of treatment
for their primary disease. They can also arise from pregnancy, prior transplantation, or bacterial infections that
induce cross-reacting antibodies to HLA epitopes (170).
As noted in section IIB1, this high level of antibody reactivity can lead to hyperacute rejection and therefore poses
an additional obstacle to transplantation that must be
overcome. High panel-reactive antibody status can be
overcome either by selecting the donor graft on the basis
of nonreactivity to recipient preformed antibodies or possibly by immunoabsorption of the host’s preformed antibodies before transplantation.
Recent studies in animals suggest that presensitization by transfusion can also be prevented. Mice transfused
with donor cells in the presence of CTLA4-Ig, a molecule
that blocks costimulation, failed to generate antidonor
antibodies capable of mediating accelerated rejection
(340). To prevent sensitization, current clinical protocols
for the care of transplant candidates call for removal of
white blood cells before blood transfusion or concurrent
treatment with immunosuppressive agents.
11. Natural antibodies and complement
Natural antibodies appear to have a role only in xenograft, not allograft rejection. The predominant natural antibodies are those directed against the a-galactosyl residues present on many nonprimate mammalian endothelial
cells. They are responsible for hyperacute rejection as
discussed in section IIB1.
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Complement appears to have a role in both allo- and
xenograft rejection. It can perforate the target cell membrane and create a lethal electrolyte imbalance. Alternatively, it can complex with bound antibody and form a
potent adhesion complex for the binding of macrophages
and neutrophils, thus targeting these cells to the graft.
These functions of complement depend on the generation
of an immune response to the graft that leads to antibody
formation and antibody-complement complex formation.
12. Cytokines
Cytokines can play both destructive and immunomodulatory roles in graft rejection (264). Cytokines that
participate in rejection include TNF-a, interferon-g (IFNg), and interleukin (IL)-1 (8, 273). They contribute to graft
destruction either directly or by activating effector cells.
Cytokines thought to be capable of impairing graft rejection include IL-4, IL-10, and transforming growth factorb (TGF-b).
A contemporary controversy in immunology and
transplantation concerns the roles of specific T-cell subsets, termed Th1- and Th2-type T cells, in graft rejection
(4). The Th1-type CD4/ T cells are producers of IL-2, IFNg, and TNF-b (also known as lymphotoxin). These cytokines can activate both T cells and macrophages. They can
promote cellular immune responses that serve as terminal
effector mechanisms in allograft rejection. It has also been
suggested that expression of the IL-12 receptor b2-subunit
is specifically restricted to the Th1-type of cells (332, 406).
Interleukin-12 is a proinflammatory cytokine produced
predominantly by activated macrophages. The Th1-type
immune responses are proinflammatory, promoting CTL
development, delayed hypersensitivity responses, and the
production of the IgG2a antibody that is involved in
ADCC.
In contrast, Th2-type cells produce IL-4, IL-5, and IL10, cytokines thought to have immunosuppressive or
downregulatory effects on the immune system. It has been
suggested, however, that in the absence of CD8/ T cells,
CD4/ T-cell production of Th2-type cytokines can also
mediate graft rejection (56). Whereas Th1-type immune
responses are proinflammatory, Th2-type immune responses are biased toward humoral, IgE-mediated allergic, and mucosal immune responses (264).
The Th1- and Th2-type cytokines are not simply the
end products of an immune response; they can also, depending on the sequence and intensity of their production,
determine (or ‘‘polarize’’) the nature of an immune response. T cells exposed to antigen (e.g., grafts) in the
presence of IL-4 are driven toward Th2-type immune responses. In contrast, exposure to antigen in the presence
of IFN-g directs T cells toward a Th1-type response. The
IFN-g accomplishes this polarization by preventing the
differentiation of naive cells to Th2-type cells despite the
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presence of IL-4; IL-12, when available, then drives the
cells toward a Th1-type response (406). Interleukin-12 appears to be a potent determinant of Th1- versus Th2-type
polarization of the immune response to foreign tissue.
13. Current status of the Th1-Th2 paradigm
The Th1-Th2 paradigm as formulated in mice, however, has begun to break down in its translation to the
human immune response. For example, the expression of
IL-10 seems to be restricted to Th2 clones in mice,
whereas in both humans and rats, IL-10 is expressed by
both Th1 and Th2 clones. Moreover, cells other than CD4/
T cells can express IL-10 (79).
Mosmann and Kelso suggest that the attribution of
graft acceptance versus graft rejection to predominance
of a Th1- over a Th2-type immune response may represent
an oversimplification of in vivo events (167a, 264). They
point to the redundancy of cytokines able to mediate a
particular effect and the pleiotropic nature of individual
cytokines. The Th1-Th2 paradigm nonetheless remains
useful in the interpretation of many aspects of the immune
response to foreign tissues.
109
sence of a detectable immune response to a functional
graft in the absence of immunosuppression.
The functional definition of tolerance is based on
graft outcome. Tolerance in immunologic terms, however,
may not be induced in all recipients of successful grafts.
There are many reports of animals and humans bearing
intact and functional grafts in the absence of immunosuppression while at the same time retaining demonstrable
host versus graft immune reactivity (119, 385). In addition,
a common feature of grafts in ‘‘tolerized’’ recipients is the
presence of a mononuclear infiltrate (120, 380). It is unclear whether these infiltrates are destructive or protective, and it is possible that these cells play a role in the
maintenance of the tolerant state.
The three functional hallmarks of immunologic transplantation tolerance are 1) the lack of demonstrable immune reactivity to graft alloantigens, 2) the presence of
immune reactivity to other alloantigens, and 3) absence
of generalized immunosuppression for graft maintenance.
The immunologically tolerant graft recipient retains a
functional graft, retains immune reactivity to all other
foreign antigens, and avoids the risks associated with generalized immunosuppression.
III. IMMUNOLOGIC TOLERANCE
C. Genesis of the Concept of Transplantation
Tolerance
A. New Approaches to Transplantation
The immune response to allo- and xenografts reviewed above is remarkably complex and redundant. Indeed, even drugs that induce a state of general immunosuppression by interfering with many elements of the immune system are still incapable of preventing rejection
when MHC mismatches are extensive. It is no wonder
that precisely targeted, limited interventions capable of
inducing graft acceptance have proven elusive. There remains no question, however, that alternative approaches
to transplantation that circumvent the morbidity and mortality inherent in generalized immunosuppression are required.
Based on the recent discoveries in immune system
recognition and activation, an appealing alternative approach to transplantation is the induction of tolerance to
the foreign tissue. Tolerance induction is viewed by many
as the most promising alternative to immunosuppression
(93, 149, 314, 342, 373, 420).
B. Definition of Tolerance
Transplantation tolerance may be defined in two
complementary ways. It is defined ‘‘clinically’’ or ‘‘functionally’’ as the survival of foreign (allogeneic or xenogeneic) tissue in normal recipients in the absence of immunosuppression. It is defined ‘‘immunologically’’ as the ab-
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One of the first insights into the immunologic basis
of transplantation tolerance was the description by Owen
(294a) of freemartin cattle. These cattle are not monozygotic, but because of placental anatomy, they share a common circulation during gestation. Owen’s observation was
that pairs of freemartin cattle mutually accept allografts
without the need for immunosuppression. Billingham et
al. (27) then extended this observation by demonstrating
that graft tolerance could be induced by exposure of neonatal animals to allogeneic cells. Based on these and other
observations, Burnet (47) proposed the clonal selection
theory to explain how the immune system distinguished
self from nonself. Clonal deletion remains one of the major theories of immunologic tolerance today.
Burnet’s theory proposes that clonal selection deletes
all self-reactive immune cells in central lymphoid organs
like the thymus before their release into the circulation.
This theory predicts that all self-reactive cells are deleted
before release into the periphery and, by definition, all
activation of the normal peripheral immune system must
be in response to the detection of nonself antigens. A
corollary of the Burnet theory would be that elimination
or reeducation of the subset of immune system cells that
recognize a specific foreign graft should permit long-term
tolerance of a graft in the absence of immunosuppression.
It is now recognized, of course, that clonal deletion
alone cannot explain all aspects of self-tolerance. Self-
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reactive lymphocytes and autoantibodies have been detected in circulation of healthy individuals. These observations have required the development of new (but complementary) theories of tolerance based on suppression, lack
of appropriate costimulation, and microenvironmental
factors that prohibit self-reactive cells from mediating an
immune response. These newer theories, in turn, have
suggested additional potential mechanisms for inducing
long-term tolerance of a graft in the absence of immunosuppression.
Most such theories have continued to be based on
the Burnet self-nonself paradigm, but the concept of the
immune response as recognition of ‘‘nonself’’ has recently
been reinterpreted in terms of response to the recognition
of ‘‘danger’’ (249). This theory holds that when tissue is
damaged (e.g., by infection), molecular signals inform the
immune system that danger is present and an appropriate
local response is mounted. The theory is based largely
on the evolutionary argument that tissue damage would
indicate an infection and therefore require an immune
response to eliminate the infectious agent. Resolution of
the infection would halt tissue damage and ensuing danger signals, and the immune response would recede. This
theory predicts that well-healed, quietly functional grafts
may not generate danger signals and may be able to survive in the absence of immunosuppression.
The richness of the immune response and the theories that have developed to explain self-nonself discrimination suggest that a broad range of strategies may have
the potential to induce long-term tolerance of a graft in
the absence of immunosuppression. These theories and
the strategies that they have inspired are discussed in
section IIID.
D. Graft-Based Tolerance Induction
1. Fetal tissue and MHC knockouts
One obvious strategy for the induction of tolerance
to a graft is to reduce its antigenicity, i.e., its ability to
provoke a host immune response. Many approaches to
the reduction of graft antigenicity have been investigated.
The focus of most interventions has been the donor MHC.
Much research has centered on the use of fetal tissues
because they express lower levels of MHC antigens than
do adult tissues (386). Because of the highly experimental
nature of the concept and the unresolved ethical issues
that surround it, few transplants of fetal human tissues
have been attempted. One example is the use of fetal
tissues to treat Parkinson’s disease (3, 178, 179).
The available animal data suggest that, although the
antigenicity of fetal tissues may be less than that of corresponding adult tissues, the reduction in antigenicity is not
enough by itself to ensure permanent graft survival (237,
239, 386). The concept remains intriguing, however. In
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animal research, proof-of-concept experiments have used
knockout mice that do not express any MHC class I or
MHC class II molecules (130), but graft survival was not
permanent. Application of this technique to humans
would require the development and implementation of
xenogeneic knockouts and protocols for transplanting genetically manipulated animal organs.
2. Masking
Another approach to modulating the antigenicity of
the donor graft has been to ‘‘mask’’ the relevant immunologic recognition sites on transplanted tissues. Human
pancreatic islet xenografts have been successfully transplanted into mice without immunosuppression simply by
coating the donor islets with F(ab*)2 fragments of antiHLA class I antibody or antibody to tissue-specific epitopes (94). To date, however, no clinical reports of the
successful use of this approach in humans have appeared.
3. Privileged sites
Immunologically privileged sites in hosts that permit
transplantation of grafts without the requirement for immunosuppression have been recognized for more than 50
yr (115, 275, 371). Immunologically privileged sites include the brain, testis, mammary and subcutaneous fat
pads, thymus, anterior chamber of the eye, matrix of hair
follicles, and the uterus during pregnancy. In Syrian hamsters, the cheek pouch has also been investigated as an
immunologically privileged site.
Many explanations of immunologic privilege have
been offered. These have included a blood-tissue barrier
that prevents access by the immune system to the site.
This explanation is particularly relevant to privileged sites
in the central nervous system. Other explanations have
included 1) high concentrations of suppressor cells at
the site, 2) soluble molecules secreted by the tissue that
modulate local immune responses, and 3) imprisonment
of graft antigens within the site, precluding a peripheral
immune response.
Immunologically privileged sites can also exhibit at
least two characteristics that differentiate them from
other sites. First, extracellular fluid within these sites generally does not drain directly via lymphatics into lymph
nodes, the site where host immune responses are typically
initiated. Second, the extracellular fluid in such sites can
contain high concentrations of cytokines such as TGF-b, a
potent immunomodulatory cytokine that directs immune
responses to nondestructive Th2-type rather than Th1type responses.
Additional factors must, however, be involved, because infection in the privileged site does induce effector
cell infiltration and local immune system activation. In
addition, many grafts in privileged sites will survive de-
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spite the presence of an infection and nonspecific inflammation in the site.
At least four additional immunologic mechanisms
have been invoked to account for the increasingly complex transplantation biology associated with these sites
(392). Depending on the site, these include clonal deletion,
clonal anergy, immune deviation, and T-cell suppression,
each of which is discussed in a broader context below.
None of these mechanisms is mutually exclusive.
A) ANTERIOR CHAMBER-ASSOCIATED IMMUNE DEVIATION.
Transplantation of human corneas does not require immunosuppression, and for this reason, successful grafts of
this tissue actually antedate the first human kidney grafts.
These transplants were successful, at least in part, due to
the presence of anterior chamber immune privilege (392).
This system has been studied extensively, and it has been
determined that privilege exists in part because antigens
introduced into the eye are captured by distinctive APC
that migrate via the blood to the spleen. There they generate a systemic immune response that is biased against the
Th1-type CD4/ T cells that mediate delayed hypersensitivity and that help B cells to secrete complement-fixing
antibodies. These APC do, however, stimulate CD8/ T
cells that function as regulatory cells.
The term anterior chamber-associated immune deviation has been coined to describe this immune response. It appears to be mediated by antigen-specific regulatory T cells that secrete TGF-b in an autocrine fashion
and suppress effector functions of proinflammatory Th-1type CD4/ T cells. Recent data suggest, however, that
FasL (CD95L) expression by host cells is also involved in
the maintenance of immunologic privilege at this site (126,
394). It is possible that two or more mechanisms may
simultaneously be involved.
B) ROLE OF FAS-FASL (CD95-CD95L) IN IMMUNOLOGIC PRIVILEGE.
Many activated cells express Fas (CD95), a cellsurface molecule belonging to the TNF family (267). When
cells expressing Fas encounter cells expressing the counterreceptor FasL (CD95L), the binding of Fas and FasL
leads the cell expressing Fas to undergo programmed cell
death by apoptosis. The process is thought to be important generally in the modulation and termination of
inflammatory immune responses. Because activated graftreactive T cells express Fas, it was hypothesized that immunologic privilege might involve the expression of FasL
within the privileged site.
The role of Fas-FasL interaction in immunologic privilege was first documented by the discovery that testis
allografts survive indefinitely upon transplantation to allogeneic hosts and that this survival is associated with the
expression of FasL (22). Testes from mutant gld mice with
defective FasL expression do not survive in allogeneic
hosts. Further analyses showed that FasL mRNA is constitutively expressed by testicular Sertoli cells and that Sertoli cells from normal mice, but not gld mutant mice (de-
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ficient in FasL), are accepted when transplanted into allogeneic recipients. Expression of FasL in the testis is
thought to provide immunologic privilege by inducing
apoptotic cell death in Fas-expressing recipient T cells
that become activated in response to graft antigens (22).
C) ARTIFICIAL IMMUNOLOGIC PRIVILEGE. The ability of
Sertoli cells to express high levels of FasL (CD95L) has
prompted attempts to use them to provide immunologic
protection for other transplanted tissues in a kind of artificial immunologically privileged site. A mixture of Sertoli
cells with islets before transplantation into the renal subcapsular space reportedly results in islet allograft survival
in the absence of immunosuppression (364).
Further evidence consistent with a role for FasL
(CD95L) expression on graft survival, and with the concept of artificial immunologic privilege, was provided by
Lau et al. (204). These authors expressed FasL on myoblasts, mixed the myoblasts with islets, and observed indefinite islet allograft survival in the absence of immunosuppression in chemically diabetic mice. Graft survival
was not prolonged by mixtures of islets and unmodified
myoblasts or Fas-expressing myoblasts. Close proximity
of FasL-expressing myoblasts and grafted islets was required; islet allografts were rejected if the FasL-expressing myoblasts were placed in the contralateral kidney.
The data were interpreted to suggest that the FasL signal
provided site- and signal-specific protection of islet allografts.
The generation and maintenance of FasL-based artificial immunologic privilege is unlikely to depend solely
on the FasL signal, however. For example, the site selected for the generation of artificial immunologic privilege affects the ability of FasL-expressing cells to survive.
In one study, transfected hamster kidney cells expressing
FasL survived indefinitely in the subrenal space but not
subcutaneously in xenogeneic nude mouse recipients.
This outcome was hypothesized to result from a FasLmediated inflammatory reaction induced when the graft
was placed subcutaneously but not subrenally (450). Expression of FasL is known to be able to generate a severe
inflammatory reaction (5, 450).
Involvement of factors other than the FasL signal in
artificial immunologic privilege has also been suggested
by Allison et al. (5), who were unable to confirm the report
of prolonged survival of subrenal Fas-L/ testis allografts
mentioned above (22). Failure of Fas-L/ testis allografts
has also been reported by others (386, 387).
Other attempts to exploit graft expression of FasL to
achieve transplantation tolerance in the absence of immunosuppression have also failed (64, 163). Transgenic mice
were engineered to express FasL under the control of the
b-cell-specific rat insulin promoter. In three experiments,
expression of FasL on islets not only failed to prevent
rejection but actually appeared to accelerate graft destruction. Graft destruction was due to expression of Fas
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by b-cells in the presence of activated T cells, resulting
in b-cell self-destruction (64). Furthermore, in the FasLexpressing transgenic mice, a pancreatic granulocyte infiltration developed, suggesting that FasL expression may
have proinflammatory activity when expressed in specific
tissues (5). These observations have prompted cautious
reevaluation of the use of FasL-expressing cells to induce
artificial immunologic privilege for transplantation tolerance induction.
E. Host Response-Based Tolerance Induction
Induction of transplantation tolerance by altering
host responses to the graft fall into two general categories,
central and peripheral. We discuss each in detail, but before doing so, we review the mechanisms of T-cell activation that are central to all of the strategies in each category.
1. The two-signal hypothesis
How immune responses are initiated has been investigated intensively, and historically, many of the investigations have been tied closely to transplantation biology.
Nearly 30 yr ago, Bretscher and Cohn (43) observed that
presentation of antigen to the immune system was necessary but not in itself sufficient to initiate an immune response, in that case the production of antibody by B cells.
Based on this finding, they proposed the concept of functional deletion or ‘‘paralysis.’’ They introduced a model
for B-cell activation that featured a requirement for two
signals to achieve activation (43).
Bretscher and Cohn (43) proposed that recognition
of antigen by a B cell (signal 1) sent a signal that, in the
absence of any further intervention, would paralyze the
cell. To overcome this paralysis in appropriate circumstances, they proposed that simultaneous delivery of a
second signal would induce B-cell responsiveness. They
hypothesized that signal 2 came from a T cell. Signal 2
is now termed ‘‘costimulation.’’
The ‘‘two-signal’’ concept was extended to T-cell activation some 5 yr later by Lafferty et al. (192), who proposed that T cells require not only the recognition of antigen in the context of MHC (signal 1) but an additional
signal (signal 2) to become fully activated (192). They
proposed that signal 2 came from hematopoietic cells,
specifically APC. The proposal was based on the finding
that survival of allogeneic thyroid grafts was prolonged if
the tissue was first cultured in vitro for several days to
remove passenger leukocytes, i.e., APC. Their observations were quickly extended to islets, and it was shown
again that culture to remove passenger leukocytes prolongs allogeneic islet graft survival (21, 411).
The two-signal concept was further developed in in
vitro experiments, demonstrating that the delivery of sig-
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FIG. 3. Depicted in schematic form are basic principles of T-cell
activation in response to presentation of alloantigen by APC. Process
occurs in 3 steps. The 1st step is alloantigen recognition: engagement of
TCR by MHC-antigen complex on an APC. Engagement of TCR generates
signal 1, which then induces CD154 (CD40L) expression on responding
T cell. The 2nd step, induction of CD154, permits engagement of CD40
on APC and is termed coactivation. Engagement of CD40, in turn, upregulates costimulatory molecules B7–1 and B7–2. As a consequence of
increased expression of B7–1/2, APC reciprocally triggers T cell via
CD28, a process termed signal 2 or costimulation. Activated allospecific
T cell now becomes an effector cell capable of mediating allograft rejection. In absence of signal 2 or coactivation via CD40-CD154 that precedes it (step 2), T-cell activation does not occur. Also depicted is
CTLA4, a second ligand for B7–1/2 that, unlike CD28, is not constitutively expressed on T cells. Role of CTLA4-B7–1/2 interactions in T-cell
activation is controversial (see sect. IIIE1C).
nal 1 (antigen) to T cells in the absence of signal 2 (costimulation) shut down IL-2 production, downregulated TCR
expression, and induced a state of nonresponsiveness
termed anergy (159, 265, 330, 352, 355–357).
The process of activating T cells by MHC plus peptide
(signal 1) and costimulation (signal 2) is now understood
at the molecular level and is known to be more complex
than originally thought. To achieve full T-cell activation,
three (not two) receptor-ligand interactions must occur.
The first interaction is antigen-specific binding of the TCR
to peptide-MHC complexes (signal 1). The second is binding of CD154 (CD40 ligand) on T cells to CD40 on APC
(coactivation). The third is binding of B7–1/2 on APC to
CD28 on T cells (signal 2, costimulation). With certain
exceptions not germane to our discussion of tolerance,
these three interactions characterize the T-cell response
to foreign tissue. These three steps leading to T-cell activation are depicted schematically in Figure 3.
The MHC-peptide-TCR interaction (signal 1) was described in Figure 2 and section IIC5. The coactivation and
costimulatory interactions are described below.
A) CD40-CD154 (CD40L) COACTIVATION. Antigen-specific ligation of the TCR with a specific peptide-MHC complex
(signal 1) induces the rapid but transient upregulation of
CD154 (also called gp39 or CD40 ligand) on the surface
of the T cell. The expression of CD154 on T cells then
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permits the T cell to activate APC (principally the one
that is delivering signal 1). This occurs through the interaction of constitutively expressed CD40 on the APC with
the newly expressed CD154 on the T cell (197, 277, 295,
381). CD154 is a glycoprotein expressed predominantly
on the surface of activated CD4/ T cells (277, 295), but
also on other types of activated cells (66, 103, 195).
B) B7 – 1/2-CD28 (CD80/CD86-CD28) COSTIMULATION. The engagement of CD40 with its ligand, CD154, results in the
rapid upregulation of the B7–1 and B7–2 costimulatory
molecules on the surface of APC (66, 103, 168, 319). The
upregulation of B7–1/2 (CD80/CD86) comprises the signal 2 postulated by Lafferty et al. (192) to be required for
T-cell activation. This signal is actually transduced to T
cells by the receptor-ligand binding of newly expressed
B7–1/2 on APC with constitutively expressed CD28 on T
cells. Encounter of T cells with antigen in the absence of
costimulation by B7–1/2 through CD28 results in their
failure to become activated (59, 159, 220, 221, 357, 409,
414). These processes are depicted schematically in Figure 3.
C) CTLA4-B7 – 1/2 COSTIMULATION. A second receptor for
B7–1/2 on T cells has been discovered and designated
cytotoxic T lymphocyte antigen-4 (CTLA4) (44, 221, 357).
This CTLA4 is upregulated on T cells 48–72 h after their
activation by encounter with antigen and CD40-CD154 coactivation. Expression of CD28, in contrast, is constitutive. The CTLA4 binds to B7–1/2 with 10- to 100-fold
greater affinity than does CD28 (165, 357).
The role of CTLA4 in regulation of T-cell activation is
a subject of considerable interest and controversy. CD28
binding to B7–1/2 is generally believed to deliver signal
2 to T cells and complete the process of T-cell activation.
CTLA4 binds to B7–1/2 with higher affinity than does
CD28 and competes with CD28 for this ligand. Binding of
CTLA4 to B7–1/2 is thought by some to deliver additional
costimulation and by others to interfere with costimulation and to deliver a downregulatory signal.
Many lines of evidence are consistent with the hypothesis that CTLA4 downregulates activated T cells (165,
184, 413, 417). The most convincing evidence has been
provided by CTLA4 knockout mice (415, 434). These animals develop a severe lymphoproliferative disease and die
early in life. The disease can be prevented by administration of CTLA4-Ig fusion protein, a hybrid molecule that
blocks B7–1/2 interaction with CD28. Cessation of
CTLA4-Ig treatment leads to recrudescence of the lymphoproliferative disease and death (416).
Another study has shown that anti-CTLA4 antibody
treatment of young transgenic mice with a diabetogenic
TCR is permissive to the expression of autoimmune diabetes (231). Treatment of mice with anti-CTLA4 monoclonal
antibody (MAb) has also implicated CTLA4 as an important downmodulator of T-cell activation. Treatment
with a blocking anti-CTLA4 MAb is permissive to in-
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creased T-cell proliferation (222); a different anti-CTLA4
MAb can induce apoptosis of T cells, the ultimate form
of downregulation (125). Ligation of CTLA4 may also deliver a signal that is necessary for tolerance induction,
another manifestation of the downregulation of T-cell activation (187, 243, 305).
Although these data strongly suggest that CTLA4 acts
primarily to downregulate immune responses, other data
suggest that the opposite effect may occur in certain circumstances. For example, CD28-deficient mice can activate T cells and induce their proliferation through the
CTLA4 molecule (448). Moreover, the antibodies used to
define an immunomodulatory role for CTLA4 may in fact
be blocking antibodies that prevent the enhancement of
T-cell responsiveness by CTLA4 (223).
D) THE B7 FAMILY OF COSTIMULATORY MOLECULES. The
expression of B7–1 (CD80) and B7–2 (CD86) follow different kinetics. The molecules appear at different times
during the development of an immune response (144,
449). Costimulation provided through these molecules
may generate different cytokine profiles in stimulated T
cells (107, 185). Ligation of CD28 by CD86 appears preferentially to induce expression of IL-4, a Th2-type cytokine,
whereas ligation of CD28 by CD80 appears to induce a
less biased cytokine profile.
The CD80/CD86 system is growing in complexity. Expression of CD80 and CD86 may be differentially regulated by cytokines in the microenvironment in which they
interact with CD28 (202). Antibodies to B7–1 and B7–2
have differential effects on immune responses, especially
on autoimmune responses (185, 213). In addition, at least
three forms of CD80 have been identified in mice (16, 40,
106, 133, 143, 154, 155). Molecules in this B7 family are
designated B7–1, B7–1a, and B7–1cytII. These molecules
exhibit differential and variable expression, diverse immune response effects, and a range of binding affinities
to CD28 and CTLA4. The differential activity of each in
relation to the provision of costimulation is yet to be determined (34, 300).
For the purposes of this review on induction of transplantation tolerance, the key observation is that blockade
of B7-CD28 interaction has potent immunosuppressive
and perhaps tolerance-inducing properties in allograft and
xenograft transplantation (see sect. IVA8).
E) ACTIVATION OF NAIVE VERSUS MEMORY CELLS. We conclude this discussion of the two-signal model with the
observation that costimulation (and cytokine) requirements for activation of naive versus memory T cells are
very different. The former have never been activated; the
latter have been activated by antigen exposure and retain
the memory of that exposure. Much more stringent criteria must be met for the activation of naive T cells than
for the reactivation of memory cells (41, 87, 403).
In addition, as noted in section IIE12, the immune
response of T cells following activation can be biased
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toward either Th1- or Th2-type effectors as a function of
cytokine milieu in which they first encounter antigen
(402). Together, these observations have practical implications for transplantation tolerance protocols that involve polarization of the immune response toward nondestructive Th2-type reactivity.
Naive T cells display higher requirement for antigen,
need stronger costimulatory signals, and rely more heavily
on the presence of enhancing cytokines for activation
than do memory T cells (70). With current technology, it
is difficult, if not impossible, to tolerize memory cells in
transplantation.
As described in section IV, almost all successful tolerance-induction methodologies employ techniques to prevent the activation of naive T cells. If presensitization of
the T-cell immune system has occurred due to previous
transplants or exposure to multiple transfusions, adjunct
therapy to eliminate the preexisting memory T cells is
routinely required for tolerance induction.
2. Central tolerance
Tolerance to self at the T-cell level occurs during
differentiation of T cells in the thymus. In this organ, T
cells develop their TCR repertoire, and selection against
self-antigen responsive cells occurs by both positive and
negative processes. T cells must first recognize self-MHC
to permit their survival (positive selection). If the affinity
of TCR binding to self-MHC is too strong, however, the
cells are thought to be clonally deleted (negative selection).
A) CLONAL DELETION. The classical form of endogenous
self-tolerance requires the deletion of self-reactive T lymphocytes in the thymus (32, 164). The clonal deletion of
developing T cells involves deletion of immature
CD4/CD8/ thymocytes after they first express their TCR
on the cell surface. This process has been elegantly demonstrated by following the intrathymic development of
specific populations of developing T cells that express
unique naturally occurring TCR Vb sequences or a
transgenic TCR that is directed against self-antigen (172).
The clonal deletion mechanism of tolerance postulates that all self-reactive T cells are eliminated before
their migration to peripheral tissues. This mechanism predicts that the introduction of transplantation antigen into
the thymus should result in the selective deletion of all T
cells reactive to that antigen and should therefore induce
tolerance. This hypothesis has been tested and, as described in section IVA4, is a potent method for inducing
transplantation tolerance.
It is unlikely, however, that the immune system relies
solely on clonal deletion to maintain tolerance. Self-reactive T cells do, in fact, escape from the thymus to the
periphery, but in most individuals, they do not lead to
immune reactivity against self. Furthermore, central toler-
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ance cannot explain 1) how self-reactive cells are eliminated if the peripheral antigen is not expressed intrathymically, 2) how tolerance to cryptic intracellular antigens
is achieved, or 3) how tolerance is generated to antigens
to which the immune system is exposed late in life.
Given that that prevention of self-reactivity without
compromising the ability to mount a danger response is
so critical, it is not surprising that tolerance induction is
a redundant process both in the thymus and in the periphery. Immunologists have recently exploited this redundancy to develop multiple approaches to the induction of
transplantation tolerance. One such redundant intrathymic mechanism is clonal inactivation.
B) CLONAL INACTIVATION. Clonal inactivation is a nondeletional mechanism of self-tolerance that occurs intrathymically (318). Tolerance by inactivation involves radiation-resistant thymic stromal elements, perhaps thymic
epithelial cells (150, 353). Self-reactive cells tolerized by
this process are described as ‘‘clonally anergic.’’ Anergized, clonally inactivated antigen-reactive T cells persist
in the host, but they do not become activated in response
to antigen presentation. This form of T-cell nonresponsiveness has been exploited for the induction of transplantation tolerance in the peripheral immune system to
which we turn next.
3. Peripheral tolerance
Peripheral tolerance is based on the observation that
self-reactive T cells that escape into peripheral tissues
appear to be held in check by immunomodulatory controls. Multiple components of the peripheral tolerance
process have been identified. These have yielded several
approaches to the induction of transplantation tolerance.
The specificity and safety of each approach have improved steadily.
A) ANERGY. As noted above in section IIIE2B, anergy
is defined as a state in which T cells are refractory to
activation. In the periphery, anergy is thought to occur
when T cells bind ligand in the absence of costimulation.
Anergic T cells have been documented by demonstrating
the presence of cells with a TCR directed toward the
antigen of interest that nonetheless do not respond to that
antigen in the presence of costimulatory signals. Anergy
was first suggested in 1983 (196) and formally demonstrated in 1987 (159, 265). In those studies, antigen was
presented to T cells using fixed APC which, because of
the fixation, could not upregulate B7 molecules and would
therefore not provide costimulation. The defining in vitro
characteristic of anergic cells was their inactivation by
antigen rather than their deletion. In addition, they lacked
IL-2 production (235) and evidenced downregulation of
TCR expression (177, 330, 358, 454). Finally, it was also
shown that the responsiveness of anergic cells to antigen
could be restored (‘‘rescued’’) by incubation in the presence of IL-2 (6, 26, 147).
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It is thought that anergy can be induced both intrathymically (317, 318) and in the peripheral lymphoid tissues (183, 198, 315, 330). Anergy appears to be much easier to induce in cloned T cells than in fresh antigen-stimulated cells. However, to date, there is no evidence that
tolerance by anergy induction can be applied to antigencommitted memory T cells in vivo (436).
It has also been suggested that anergic T cells not
only fail to respond to antigen upon restimulation but
may also function as suppressor T cells (105, 226). The
mechanism of this suppression is hypothesized to involve
competition for antigen presented on the surface of the
APC and competition for locally produced IL-2. As long
as antigen-reactive cells are blocked from proliferation,
they can act as suppressor cells (359). Peripheral cell suppression and its regulation of immune responses are discussed in section IIIE3C.
B) IMMUNOLOGIC EXHAUSTION. Exhaustion is a mechanism of tolerance very similar to anergy, but different with
respect to the ultimate fate of the antigen-specific T cell
(329). Immunologic exhaustion can be detected in populations of antigen-specific T cells that are initially activated
and expanding. Those populations of T cells undergoing
expansion while exposed to high concentrations of antigen were found to be inactivated (anergized), whereas T
cells exposed to lower concentrations of antigen were
observed to disappear (exhaustion). The disappearance
of antigen-reactive T cells in this setting may involve
apoptosis (30, 140, 217).
C) PERIPHERAL CELL SUPPRESSION. There has been considerable controversy over the existence, identity, and function of peripheral suppressor cells. It is not clear if suppression is mediated by a distinct population of cells or is mediated by cells that, under different conditions, can mediate
suppression, help, or cytotoxicity. It has even been suggested that suppressor cells can mediate regulation of target
cell killing either by cytokine-mediated modulation or cytotoxicity directed against other immunocytes.
Two classic examples of possible suppressor cell activity in vivo are based on studies of neonatal tolerance
maintenance and of the regulation of autoimmunity. In
classic neonatal tolerance induction protocols, neonatal
animals are injected with allogeneic donor bone marrow.
Not only is the donor bone marrow graft then tolerated,
but it can also be shown that tolerance to the donor cannot be broken by infusion of additional nontolerized syngeneic lymphocytes (334). This finding suggested the existence of an active suppressive mechanism because the
infused lymphocytes were functionally capable of mediating reactivity against the donor graft.
In studies of the regulation of autoimmunity, it has
been shown that autoimmune insulin-dependent diabetes
mellitus in both rat (259, 260, 335) and mouse (321) models can be modulated by regulatory or suppressor cells.
The suppressor hypothesis has been put forward to
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explain two important observations in transplantation.
The first is that alloreactive cells are present in animals
bearing intact grafts (9, 74, 258). In vitro proliferation and
cytotoxic activity to the specific tissue alloantigen of the
graft can be readily detected in animals bearing intact,
functional grafts. The second observation is the presence
of cellular infiltrates in grafts that are not rejected and
remain functional (9, 334). The suppressor cell hypothesis
has also been invoked to explain the apparent induction
of in vivo allotolerance by the transfer of suppressor cells
to naive animals (infectious tolerance, see sect. IIIE3D).
It has also been invoked to explain the inhibition of alloresponsiveness in naive cells that are cultured in vitro in
the presence of putative suppressor cells (78, 85, 137, 314,
334, 392).
Both CD4/ and CD8/ T cells have been implicated
as mediators of peripheral suppression (97, 137, 289, 290).
In cases of immunoregulation of autoimmunity that have
been studied, the CD4/ cell subset appears most likely
involved. In cases of the regulation of cytotoxic T cells,
the CD8/ T-cell subset has been postulated to mediate
the activity.
Several hypotheses have been put forward to explain
the mechanism by which suppressor cells regulate immune responses. One hypothesis holds that secretion by
suppressor cells of cytokines like IL-4 (312) and TGF-b
(327) modulates immune reactivity in the local microenvironment. The possibility that TGF-b functions in this way
has been termed ‘‘cytokine-mediated bystander suppression’’ (62, 63, 100, 226, 457, 458). Another possibility is
that activated T cells expressing FasL kill all activated T
cells at the site of immune reactivity, effectively downregulating the immune response (267, 459). A third alternative
hypothesis is that CD4/ suppressor cells mediate their
activity by blocking the indirect pathway of alloantigen
recognition, effectively preventing priming of the immune
system (452). Which of these proposed mechanisms, or
which combination of these mechanisms actually mediates suppression is unclear. It is also unclear whether
suppressor cells represent a unique population of cells
or normal helper and effector cell populations that are
exhibiting alternative functionality. Despite these uncertainties, however, the available data strongly support the
concept of suppressor cell activity and its importance as
a mechanism of tolerance induction.
D) INFECTIOUS TOLERANCE. The case for the existence
of suppressor cells has received additional support from
the demonstration of infectious tolerance. This type of
tolerance is characterized functionally by the ability of
adoptively transferred CD4/ cells to inhibit the ability of
naive lymphocytes to reject grafts (314). Many examples
of this type of tolerance have been documented. Most
examples invoke infectious tolerance as the mechanism
by which anti-CD4 MAb therapy may induce transplantation tolerance (292, 362) (see sect. IVA6A).
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E) CLONAL DELETION. Although central intrathymic
clonal deletion has long been recognized as a primary
mechanism of tolerance induction to self-antigens, clonal
deletion of peripheral T cells and tolerance induction has
only recently been appreciated (435). This mechanism has
been elegantly demonstrated in mice using minor lymphocyte-stimulating (Mls) superantigens that are now known
to be exogenous mouse mammary tumor viruses (2, 65,
429, 447). In these studies, exposure to Mls antigen led
first to an expansion of Mls-reactive cells that was followed by clonal deletion of the Vb6/ cells that recognized
the antigen. This mechanism was also functional for CD4/
antigen-specific T cells, demonstrating that the peripheral
clonal deletion of Mls-reactive cells is not a unique property of the Vb6/ Mls-superantigen-reactive cell population
(198).
Clonal deletion of CD8/ cells has also been demonstrated, and cytokines may play a role in this process
(361). Specifically, the Th2-type cytokines IL-4 and IL-10
have been implicated in the clonal deletion of alloreactive
CD8/ T cells that mediate graft rejection; deletion of reactive cells was confirmed using a clonotypic antibody
against the TCR expressed on the transgenic T cells used
in the experiment (361).
Finally, as discussed in section IIID3B, the interaction
between activated T cells expressing FasL (CD95L) and
activated cells, including T cells expressing Fas (CD95),
has been strongly implicated in the clonal deletion of immune response cells. Deletion of the antigen-reactive cell
population is not always required, however, for the induction of a nonresponsive immune state. An example of
nondestructive, noninactivating tolerance induction is immune deviation.
F) IMMUNE DEVIATION. As was the case for the theory
of suppressor cell function in transplantation tolerance,
there is controversy regarding the role of immune deviation in allograft tolerance and survival. The controversy
stems in part from the large number of factors that can
‘‘deviate’’ the immune response and the diversity of mechanisms that lead to the expression of those factors.
The strongest evidence for immune deviation is in
the area of control of the self-reactive autoimmune response. In autoimmunity, the deviation of an immune response from the destructive cytokines IL-2, IFN-g, and IL12 to the ‘‘suppressive’’ cytokines IL-4, IL-10, and TGF-b
is associated with disease prevention (4). As noted above,
this type of deviated cytokine response has also been
implicated in neonatal tolerance (60, 102, 111, 334), but
the importance of immune deviation in the modulation of
graft immune responses is uncertain.
One of the best-characterized instances of graft tolerance that may be mediated, at least in part, by immune
deviation is the immune privilege of the eye (see sect.
IIID3B). In the anterior chamber, it is hypothesized that,
following encounter with antigen, T cells become anergic,
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undergo apoptosis, secrete suppressive TGF-b, and release soluble regulatory factors. In addition, APC indigenous to the eye take up antigen and subsequently migrate
to the spleen where they activate a unique spectrum of
antigen-specific T and B cells. These cells generate a Th2type immune response associated with the absence of
delayed-type hypersensitivity and complement-fixing antibodies (392). Immune deviation, however, is only one of
at least four possible mechanisms that mediate ocular
tolerance, with the others being clonal deletion, clonal
anergy, and T-cell suppression (391, 392).
Transforming growth factor-b also has been reported
to have potent immunosuppressive effects in allograft survival experiments (316, 366, 430). The Th2-type cytokine
IL-10 may also play a role in immune deviation-related
graft tolerance. Interleukin-10 has many effects that may
deviate the immune response. It has been shown to prevent
APC activation and costimulation, permitting antigen presentation in the absence of costimulation and adhesion molecule expression (57, 129, 442). It may also induce an anergic state in CD4/ T cells (83), suppress production of the
proinflammatory cytokine IL-2 by CD4/ T cells (81), inhibit
T-cell proliferation (407), and regulate expression of IFN-g
and IL-4 by monocytes, dendritic cells, and Langerhans cells
(APC). The role of agents like IL-10-Fc fusion proteins to
serve as tolerogenic pharmaceuticals is under study (461).
The action of suppressor cells may also involve immune deviation principles. In studies of the adoptive
transfer of transplantation tolerance with suppressor cell
clones, it has been shown that the clones are Th2-type
cells (236). Immune deviation may also occur when costimulation is blocked. Blockade of the CD28-B7 costimulatory pathway after alloantigenic stimulation in vivo inhibits the production of Th1-type, but not Th2-type cytokines
(345).
In relation to the indirect evidence suggesting that
cytokines may downregulate the immune response, a note
of caution must be sounded. As Nickerson et al. (273)
have recently pointed out, ‘‘It is notable that in no circumstances to date has allograft tolerance been achieved via
specifically blocking the production/effects of a proinflammatory cytokine (e.g., IL-2), and/or enhancing the endogenous production or local/systemic administation of a
cytokine with immunoregulatory properties (e.g., IL-4, IL10, TGF-b).’’
Whether the cytokines detected at the site of graft
acceptance or rejection are causally related to the ongoing
local immune response is uncertain. The cytokine profiles
could 1) arise as a result of a tolerant state induced by a
different mechanism, 2) contribute ancillary support for
the maintenance of a tolerant state, or 3) arise independently as a consequence of the tolerant state (308).
Many studies argue strongly against a primary role
for immune deviation in graft survival. In many cases of
tolerance induction to grafts, the cytokine profile exhibits
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neither a Th1- nor Th2-type bias (161, 201). Many attempts
to skew the cytokine immune response and induce tolerance have failed (56, 423, 428, 461). Administration or
expression of IL-10 and IL-4 have not been associated
with tolerance induction (274, 461). In addition, inhibition
of Th1-type cytokines and induction of Th2-type cytokines
by blocking IL-12 fail to induce tolerance (307).
Interleukin-2, a Th1-type cytokine, has a potentially
important role in graft rejection because activated T cells
require it for proliferation. Interleukin-2 does, in fact, appear to exert a detrimental effect on transplantation tolerance induction. Administration of IL-2 as an adjunct to
various tolerizing regimens appears to preclude long-term
graft survival (73). Conversely, blockade of IL-2 binding
to its receptor on activated T cells may be a promising
approach for induction of transplantation tolerance. AntiIL-2 receptor antibodies are in preliminary clinical trial
(273), but a cautious approach is necessary. The theoretical possibility exists that the antibodies will destroy all
activated T cells and render the patient susceptible to
infection, similar to generalized immunosuppression. In
addition, the potential of IL-2 blockade to prevent allograft
rejection is uncertain given that IL-2 knockout mice reject
islet allografts with the same rapid kinetics as do normal
mice (388).
These variable and sometimes contradictory observations may be explained by 1) the redundancy in the family
of cytokines, with various members acting as T-cell
growth factors, and 2) the pleiotropic nature of individual
cytokines (273). These biological characteristics have
dampened initial enthusiasm for cytokine manipulation
and immune deviation as viable approaches to the induction of clinical transplantation tolerance.
G) CHIMERISM. As noted earlier, the first reported case
of tolerance was in freemartin cattle by Owen (294a).
This form of tolerance is based on lymphohemopoietic
chimerism. This historic observation has been revisited
and exploited to induce transplantation tolerance experimentally in both rodents and primates (see sect. IVB). The
mechanism of tolerance of this type requires chimerism
in the antigen-presenting cell compartment and, specifically, in the dendritic cell compartment (384, 385).
Passenger leukocytes present in a graft are now
known to induce a state of microchimerism in the recipient. In these microchimeric graft recipients, donor-tissuespecific hyporesponsiveness has been documented; it appears to correlate with engraftment of donor cells within
the transplanted tissue (322, 455) and with graft survival
(323). Donor-derived dendritic cells are hypothesized to
emigrate from the donor graft and to migrate to lymphoid
tissues of the host where the tolerance-inducing effect is
mediated (306).
Donor bone marrow transplantation has been used
as an adjunctive therapy to augment donor-cell chimerism
in recipients of kidney, liver, heart, and pancreas trans-
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plants (46, 101, 216, 384). More recently, this procedure
has been applied to human islet and lung transplantation
(53, 306), and its use has been proposed for induction of
xenograft tolerance (153).
The use of microchimerism to induce tolerance is not
without controversy. The available data have alternative
interpretations. The controversy revolves around the
question of whether the chimerism observed in long-term
graft survival recipients is the cause or the consequence
graft survival (446). In addition, some investigators have
failed to confirm the presence of the peripheral chimerism
in long-term graft recipients reported in earlier studies
(397). These investigators have offered an alternative explanation for the persistence of donor-origin cells in tolerized graft recipients. They argue that the tolerance observed after donor bone marrow administration is in fact
‘‘high dose, activation-associated tolerance,’’ a form of
clonal deletion (29, 263, 435). The postulate in these studies is that graft reactive cells are strongly activated, and
this strong activation leads to clonal deletion. Additional
experimentation will be required to establish the relative
importance of chimerism in transplantation tolerance.
H) IGNORANCE. As discussed in section IIIE2A, clonal
deletion in the thymus is not a completely effective process. To deal with self-reactive (and by extension graftreactive) T cells, the immune system has developed multiple redundant mechanisms for establishing and maintaining peripheral tolerance (10, 254). ‘‘Ignorance’’ is
another such mechanism. The persistence of graft-reactive T cells in recipients of functioning allografts has led
to the proposal that the T-cell immune system simply ‘‘ignores’’ the graft. The difference between ignorance and
tolerance is the ease with which the nonresponsive state
can be broken and the graft rejected.
Classical approaches to the breaking of immunologic
ignorance include infection (284, 285) and the presentation of graft antigen in combination with professional APC
(68). An example of ignorance is provided by transgenic
mice with a TCR that recognizes the glycoprotein
of lymphocytic choriomeningitis viral (LCMV) and
transgenic expression of that glycoprotein in the host’s
pancreatic islets by placing the transgene under control
of the insulin promoter (285). The antigen-specific T cells
in the host fail to mount an immune response against the
LCMV protein present on the islets. The initial nonresponsiveness, or ignorance, is thought, perhaps, to be due to
the inability of the islets to both present antigen and provide costimulation. However, infection with LCMV leads
to a rapid immune response against the live virus and to
the destruction of the islet cells expressing the LCMV
protein (284). The persistence of the antigen-reactive T
cells in a nonresponsive state until active viral infection
may mimic the situation in transplantation, where a graft
survives in the presence of circulating alloreactive T cells,
i.e., the presence of ignorance.
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I) VETO CELLS. Transplantation tolerance may also involve ‘‘veto’’ cells. Such cells are defined functionally by
their ability to serve as targets of alloantigen-specific cytotoxic T cells and then kill the cytotoxic T cell, thus vetoing
their own cytolysis (255, 405). The veto phenomenon has
been documented in many experimental models, but the
mechanism of veto cell modulation of CTL activity is uncertain. Veto activity may be due to the killing of activated
CTL, possibly via the apoptosis-inducting function of FasFasL interaction. Cytokines have also been implicated in
veto activity. In one primate study, TGF-b has been implicated in the veto of CTL activity by rhesus monkey bone
marrow cells (255).
J) ENHANCEMENT. Enhancement is antibody-mediated
prolongation of graft survival. Experimentally, enhancing
antibodies generated against the donor graft have been
shown to be effective in prolonging the survival of allogeneic heart grafts in the rat (299) and kidney grafts in the
primate (412). Anti-HLA antibodies have been shown to
enhance allograft survival (398). Enhancing antibodies appear most effective in the context of islet grafts and least
effective in the context of skin grafts (269). At this time,
the utility of enhancing antibodies in clinical transplantation is uncertain, and the possibility of antibodies detrimental to grafts has not been excluded.
IV. METHODS TO INDUCE TRANSPLANTATION
TOLERANCE IN VIVO
Volume 79
A. Methods Successful in Rodents
As was made clear in sections ID and IE, the two
major foci for tolerance-inducing regimens are donor tissue or the host immune system. Each has been manipulated with varying degrees of success, and it is possible
that combination methodologies will ultimately be required for successful translation to the clinic.
1. Graft plus generalized immunosuppression
Generalized immunosuppression is the universal
method for preventing acute graft rejection today. Generalized immunosuppression is also universally prescribed
for the maintenance of successful allografts. In theory,
however, the microchimerism induced by organ transplantation should permit withdrawal of that therapy. Only
a few such instances have been reported. The few cases
that have been reported are anecdotal and resulted from
noncompliance rather than scientific intervention (385).
There is little enthusiasm for a clinical trial of withdrawal
of immunosuppression. The consensus opinion is that tolerance is not routinely induced in graft recipients treated
with generalized immunosuppression and that continuous
therapy is required for graft survival.
As detailed above, most tolerance-induction methods
require activation, or at least ongoing involvement, of the
immune system. Almost by definition, then, the use of
generalized immunosuppression to prevent graft rejection
will pari passu preclude the induction of tolerance. The
dilemma that may soon face clinicians is whether the tolerance-inducing protocols that do not also use generalized
immunosuppression are worth the risk. The resolution of
that dilemma will be based on the outcome of animal
studies, and to those we turn next.
The preceding discussion on the theories of graftand host-based transplantation tolerance induction has
illustrated the complexity of the subject and the uncertainties faced by clinicians seeking to move transplantation ‘‘beyond immunosuppression.’’ Not surprisingly, the
myriad theories and mechanisms invoked to explain toler2. Donor-specific transfusion
ance induction and tolerance maintenance have led to
myriad approaches to the goal of enhancing the duration
Transfusion had its origins in the correction of aneof graft survival by methods that are safe.
mia, but it is now recognized that transfusion also affects
As we have noted earlier, the most promising alterna- the immune system. Beneficial effects of transfusion on
tives to immunosuppression are strategies that seek to the recurrence of cancer, postoperative infection, viral
induce donor-specific immune tolerance (131, 218, 314, infection, inflammatory disease, and pregnancy have been
369). Many of those strategies have been discussed above noted (35). As early as 1974, it was recognized that blood
in the context of the underlying theory and available evi- transfusion before kidney transplantation improved graft
dence. Their application as actual protocols to experimen- survival (293). In that seminal report, it was concluded
tal induction of tolerance has been advancing rapidly.
that ‘‘transfusions in prospective recipients lead to an imEach of the protocols discussed below has been de- provement in transplant survival, probably because of acveloped explicitly to establish a tolerant state adequate tive induction of immune unresponsiveness.’’
to support the survival of allografts. At this writing, no
The use of transfusion in transplantation focuses on
tolerance-inducing protocol has been substituted for gen- donor-specific transfusion (DST). Donor-specific transfueralized immunosuppression in the clinic. We first discuss sion has been observed to abrogate the development of
the protocols that have been reported to be successful in chronic graft rejection in mouse and rat models of transsmall-animal models and then consider protocols that plantation (80, 151, 248, 266, 294, 379, 396). The mechanism
have been successfully adapted to larger animals and underlying the unresponsive state that is induced by DST
shown to be effective in primates.
has received considerable experimental attention since the
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first reports (36, 37). Proposed mechanisms have included
immune deviation (37) and the activity of veto cells (86,
167). The improved outcome of graft survival has also been
correlated with evidence of donor-specific hyporeactivity
(323). Donor-specific transfusion has also been used in
combination with ultraviolet irradiation, another inducer
of hyporeactivity, to prolong islet allograft survival (203).
The tolerance-inducing component of the DST has
not been identified with certainty and may be different
depending on the extent of donor-host MHC mismatch.
In one study, irradiation-sensitive donor T cells (veto
cells) were required for tolerance induction to MHC class
I antigens, whereas irradiation-resistant non-T cells were
required in the DST for tolerance induction to MHC class
II antigens (426).
One cell type present in DST that has characteristics
potentially important for tolerance induction is the small
B lymphocyte. Small resting B cells are good candidates
for tolerizing T cells because they can present antigen in
the absence of costimulation. Small B lymphocytes express
only low levels of the B7–1/2 costimulatory molecules on
their surface; unless stimulated, they are ineffective as APC
(116, 158, 296). Small B cells induce tolerance when acting
as APC for protein antigens in vivo. They mediate their
tolerizing effects by inducing unresponsiveness in the
helper T-cell compartment (91, 92, 98). Small B lymphocytes also induce specific transplantation tolerance to an
MHC class II difference (151) and, in unprimed animals, to
H-Y, a minor transplantation antigen (108).
More recent protocols now combine DST with other
tolerance-inducing methodologies. In addition, it has also
been demonstrated that cells other than small B cells can
mediate the tolerizing effect of DST. These protocols are
discussed in section IVA10.
3. Peptide-based therapy
Donor-specific transfusion is a complex biologic process, rich in both peptide antigens and APC. To investigate
the antigenic specificity of the donor antigen that is important in the induction of tolerance, some investigators
have focused on peptide-induced hyporesponsiveness.
The use of peptides rather than DST permits focused investigation of the role of indirect antigen presentation in
allorecognition, since by design, the donor antigen cannot
be presented by the direct presentation pathway by donor
APC (24). Peptides of MHC class I and class II antigens
have been used to successfully induce tolerance when
administered to recipients orally (347) or with
cyclosporine A (71).
4. Intrathymic injection of antigen
Injection of soluble antigen and cellular alloantigen
injection (427) into the thymus to induce tolerance was
first demonstrated in the 1960s. The implications of this
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observation were not fully appreciated until much later.
This tolerance induction method was first applied to a
clinically relevant model of islet transplantation in 1990
(311). Intrathymic injection of allogeneic islets in combination with a single dose of antilymphocyte serum to delete preexisting alloreactive peripheral T cells led to permanent restoration of normoglycemia in a chemically diabetic recipient. This paradigm of tolerance induction
based on the intrathymic injection of alloantigen (in most
cases, intact donor cells) plus deletion of preexisting T
cells was confirmed for islets (50, 250, 310, 311) and extended to other tissues, including skin (84, 286), heart
(121, 281–283, 367), liver (49), and kidney (325).
The protocol for intrathymic injection of alloantigen
was further extended to include intrathymic injection of
peptides (287, 348) and soluble antigens (288). As was
also true of the peripheral peptide injection protocols that
succeeded DST, any tolerogenic effect of soluble antigen
injected intrathymically would have to depend on the indirect pathway of antigen presentation. Induction of tolerance using intrathymic peptides appeared to be mediated
by the induction of T-cell anergy because the tolerant
state could be broken by administration of exogenous IL2 (26, 235).
In contrast, it has been suggested that the tolerance
induced by the intrathymic injection of spleen cells results
from clonal deletion of alloantigen-reactive thymocytes
(160). Deletion of antigen-specific thymocytes following
intrathymic injection of donor cells was documented using TCR transgenic mice that were then able to tolerate a
heart allograft. Another study suggested that either clonal
deletion or clonal anergy could be important in the tolerance induced by intrathymic injection of alloantigen and
that the thromboxane A2 receptor was involved in the
process (324).
The basic intrathymic injection protocol has been extended by the application of a novel antigen delivery system. Intrathymic injection of DNA has reportedly resulted
in the induction of donor-specific tolerance (176). Interestingly, both clonal deletion and peripheral suppression,
the latter on the basis of adoptive transfer studies, were
implicated in the tolerance inducted by this protocol.
In summary, intrathymic injection of alloantigen in
combination with depletion of preexisting alloreactive peripheral T cells can induce permanent tolerance to a number of tissues and may be clinically applicable. The protocol has not yet, however, been reported to work in larger
animals or primates. In addition, the progressive involution of the thymus that occurs as humans age poses at
least a theoretical obstacle to this approach in the older
individuals most likely to require a transplanted organ.
5. Oral antigen administration
Oral tolerance has been used successfully for the
treatment of autoimmune disorders in many animal mod-
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els (437–439) and for the induction of tolerance to soluble
antigens (61, 113). Its efficacy in the treatment of human
autoimmunity remains uncertain, however, and there is
no evidence to date in any species that it can induce
allotolerance and prolong allograft survival.
6. Monoclonal antibody therapies
Monoclonal antibodies directed against cell-surface
molecules important in immune activation and response
can be used to manipulate the immune system. This approach is attractive for several reasons. Monoclonal reagents have consistent effects in multiple individuals.
They target only a single epitope on a single target molecule. Finally, the surface molecules on cells of the immune
system tend to be present across species, making a monoclonal antibody-based therapy developed in a rodent
model likely to be applicable to primates. We next briefly
consider the monoclonal antibodies that have been found
to modulate responses important in transplantation.
A) ANTI-CD4. Antigen administered in combination
with anti-CD4 MAb can induce tolerance to that antigen
(78, 341, 368, 369). Several mechanisms have been hypothesized to account for this form of tolerance induction.
The first anti-CD4 MAb studied were depleting antibodies,
and it was suggested that CD4/ helper/inducer alloreactive cells were simply deleted, resulting in the inability of
the host to respond to the foreign graft (7, 365, 368, 378).
The depleted cells were shown to be naive CD4/ cells,
suggesting that depleting anti-CD4 MAb treatment affects
non-antigen-experienced effector cells (326).
It was later shown, however, that tolerance could
also be induced using nondepleting anti-CD4 MAb, requiring new hypotheses to account for the observed results
(76, 370). Two potential mechanisms have been studied
extensively: immune deviation (28, 78, 186, 227, 320, 370)
and induction of suppressor cell activity (211, 246, 292,
362). The term infectious tolerance (see section IIIE3D)
has been used to define the suppressor cell activity that
is induced by anti-CD4 MAb treatment. It implies that the
cells of the tolerant host can inhibit the response of normal T cells to the foreign graft (292, 314).
Anergy induction may also play a role in anti-CD4
MAb-induced suppression, based on the demonstration
that the tolerant state can be broken by the addition of
IL-2 (6, 58). Other investigators, however, have failed to
find evidence of anergy following tolerance induction with
five different clones of anti-CD4 MAb (309). This observation raises the possibility that the anergy may be involved
only in a subset of cases of anti-CD4 MAb-induced tolerance.
It has also been suggested that anti-CD4 MAb can
induce Fas-mediated apoptosis of CD4/ T cells (19, 431).
This mechanism for the induction of tolerance by antiCD4 MAb has only recently been suggested, and its potential importance is uncertain.
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Regardless of the mechanism involved, anti-CD4 MAb
treatment has been shown to induce long-term survival
of islet and heart allografts in mice (6, 369) and rats (211).
Its potential as an adjunctive therapy in clinical transplantation remains to be evaluated.
B) ANTI-CD45. The CD45 family of transmembrane protein-tyrosine phosphatases plays a critical role in T-cell
signaling (55, 419, 451). Multiple alternatively spliced
CD45 isoforms, differing only in their extracellular domains, are differentially expressed by subsets of T cells
with distinct functional repertoires. Very soon after the
identification of CD45, it was observed that antibodies to
CD45 could inhibit mixed lymphocyte reactions in vitro
(141, 205). With the extension of these findings, it was
observed that antibody to CD45RB could delay renal allograft rejection in mice (206). Attempts to replicate this
observation with other clones of anti-CD45RB antibodies
were not successful, however. Initially, only antibody
from clone MB23G2 could mediate the effect, but it has
now been found that anti-CD45RB produced by multiple
hybridoma clones can prolong islet allograft survival (13).
The mechanism by which anti-CD45RB antibody induces tolerance is not known. Proposed mechanisms include differential intracellular signaling regulating IL-2 production and activation of signal pathways involving Vav in
T cells (251, 291). It has also been shown that distinct
isoforms of CD45 can differentially regulate TCR-mediated
signals (141, 251, 291). The differential regulation of Tcell activation signals may prevent the generation of an
alloimmune response or may induce other forms of tolerance based on suppression, anergy, or clonal deletion.
C) ANTI-LYMPHOCYTE FUNCTION ANTIGEN AND ANTI-INTRACELLULAR ADHESION MOLECULE-1.
Antibodies to the adhesion molecules lymphocyte function antigen (LFA) and
intracellular adhesion molecule-1 (ICAM-1) have been
shown to induce permanent heart allograft (156) and prolonged skin allograft (157) survival in mice. Anti-LFA and
anti-ICAM antibodies can also prolong rat-to-mouse cardiac xenograft survival (256) and human-to-mouse islet
xenograft survival (456). These antibodies are thought to
mediate their graft-prolongation effects not by tolerance
induction, but rather by inhibition of the migration of host
immune cells into the graft. Anti-LFA MAb has also been
used to prolong survival of transplanted myoblasts, but
in this report, host infiltration into the graft was observed,
suggesting that other mechanisms must be important
(132).
D) ANTI-MHC CLASS I. Human pancreatic islet xenografts have been successfully transplanted into mice without immunosuppression after coating of the donor islets
with F(ab*)2 fragments of anti-HLA class I antibody or
antibody to tissue-specific epitopes (94). Whether tolerance is induced using this approach or whether the host
immune system simply fails to recognize the grafted tissue
is not known.
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E) ANTI-MHC CLASS II. Administration of recipient-specific anti-MHC class II antibodies has been shown to prolong heart allograft survival in rodents (313, 376). The
anti-MHC class II antibody does not have to be cytotoxic,
suggesting that it is working via immune modulation, not
simply the depletion of activated class II/ rat T cells (376).
Anti-MHC class II antibody does not, however, prolong
skin allografts. It has been hypothesized that the effect of
antirecipient MHC class II antibody is mediated by redirection of host immune responses toward a suppressor
phenotype (38, 443).
F) IN VITRO CULTURE TO REMOVE PASSENGER LEUKOCYTES.
Donor APC present in a graft are important mediators of host immune responses via the direct antigen presentation pathway. Recognition of this important role of
graft APC led to the discovery that their removal could
have important beneficial effects on allograft survival
(134, 389). These beneficial effects on graft survival are
hypothesized to be due to the inability of the graft to
present antigen and to sensitize the recipient host immune
system. Graft APC have been removed from islet (95) and
kidney (207) allografts by pretreatment with antibody to
remove MHC class II-expressing cells. Other approaches
to remove donor graft APC include dietary manipulation
(210, 354) and, for islets, in vitro culture (245, 411).
8. Interference with costimulation
Recognition that costimulation signals are required
to achieve full T-cell activation after TCR ligation with
MHC plus antigen has led to several tolerance induction
strategies based on blockade of this interaction. The fusion protein CTLA4-Ig, which effectively blocks costimulation via CD28 by binding to B7–1/2 on APC, prolongs
kidney (14, 345), heart (300, 302, 422, 460), and islet (54,
418) allograft survival. It also prolongs the survival of
xenogeneic human islets in mice (214). Treatment of islet
allografts with CTLA4-Ig also prolongs their subsequent
survival in mice, presumably by inhibiting the ability of
passenger leukocytes to provide direct antigen presentation and costimulation (390).
The mechanisms hypothesized to be involved in tolerance induction following administration of CTLA4-Ig include suppression and immune deviation resulting from
selective inhibition of Th1-type immune responses (305,
345, 418). Treatment with CTLA4-Ig can, however, prolong
heart allograft survival in IL-4 knockout recipients, suggesting that the generation of a Th2-type immune response is not necessary for tolerance induction with this
reagent (194).
9. Interference with coactivation
As outlined in section IIIE1, coactivation describes
the interaction of CD40 on APC with its ligand CD154 on
T cells; it is an important step that precedes the induction
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of costimulation (66, 103). Blockade of coactivation in the
presence of a graft would therefore be predicted to lead
to the presentation of antigen in the absence of costimulation. This hypothesis has been tested experimentally. The
first studies using antibody to block coactivation in transplantation examined an islet transplant model (297, 337).
Transplantation of islet allografts into mice treated with
anti-CD154 MAb resulted in permanent survival of Ç40%
of the grafts. In contrast, administration of anti-CD154
MAb did not prolong skin allografts (244). The same observation was made for rat to mouse xenografts (118,
240). The reason for the prolongation of islet allografts,
but not skin allografts or xenografts was not clear. It could
have resulted from the large number of Langerhans cells
present in skin; such cells provide costimulatory activity
much more efficiently than do cells present in islets. Alternatively, the effect could have stemmed from the induction of costimulatory molecules on donor graft APC due to
tissue damage and/or nonspecific inflammatory processes
not directly dependent on CD40-CD154 interactions (244,
297, 337).
10. Combination methodologies
Combinations of immunosuppressive agents are superior to monotherapy in the prevention of acute graft
rejection. Similarly, the broad diversity of approaches to
tolerance induction, no one of which is uniformly successful as monotherapy for all grafts in all species, has led to
the evaluation of combination protocols. The goal has
been to join strategies that would act synergistically in
the induction of transplantation tolerance.
Combination therapies for the prevention of acute
graft rejection fall into two general categories. The first
combines immunosuppressive drugs with immune modulation. The second combines two or more immunomodulatory approaches that target different elements of the
immune system that participate in graft rejection. In this
section, we first describe the combined immunomodulatory approach our own laboratory has used to induce
tolerance to islet and skin allo- and xenografts. We then
compare and contrast it with combination immunomodulatory therapies that have been used by other investigators.
A) COMBINATION OF DST AND ANTI-CD154 MAB: A TWO-ELEMENT PROTOCOL FOR TOLERANCE INDUCTION.
Based on the
apparent requirement for an active immune response for
induction of durable tolerance, investigators from our laboratory have focused on a combination approach using
two tolerance-inducing methods: the administration of
DST to induce an active immune response and the
blocking of CD40 and CD154 coactivation to induce tolerance in the activated alloreactive cells. We describe this
as a two-element protocol.
Our approach to the induction of tolerance targets
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early events that accompany T-cell activation, events that
occur immediately after ligation of the TCR with MHC
plus peptide. It is directed specifically at the blockade of
coactivation by interfering with the interaction of molecules required for this process. Blockade of costimulation
inhibits the subsequent induction of B7–1/2 costimulatory
molecules on APC.
In our first experiments, we used a population of
small lymphocytes enriched for resting B cells as APC to
present alloantigen in the absence of coactivation signals
(297). Small B lymphocytes express low levels of B7–1/2
on their surface and are ineffective APC (45, 116, 124, 158,
296) (see sect. IVA2).
As described in section IIIE1, T cell-dependent activation of resting B cells leading to the expression of B7–1/
2 costimulatory molecules depends largely on the interaction of CD154 on T cells with its receptor, CD40, on B
cells (197, 277, 295, 381). CD154 on T cells is expressed
primarily by activated CD4/ T cells; it is not expressed
on resting T cells and is expressed only at low levels on
activated CD8/ T cells (277, 295). The engagement of
CD40 with its ligand, CD154, results in the rapid upregulation of B7–1/2 on B cells and other APC (168, 319). To
induce tolerance, we blocked this interaction using the
MR1 hamster anti-mouse CD154 MAb. This reagent prevents cognate T- and B-cell signaling and inhibits T-dependent humoral responses in vitro and in vivo (112, 278).
Anti-CD154 MAb prevents expression of autoimmunity in
several experimental models (66, 77, 103, 122, 195). These
include experimental autoimmune arthritis (89), experimental allergic encephalomyelitis (114, 123, 344), thyroiditis (51), lupus in murine models (72, 90, 304), and spontaneous diabetes in nonobese diabetic (NOD) mice (18). In
addition, anti-CD154 MAb impairs allo-specific CTL responses in vitro, prevents the occurrence of acute and
chronic GVHD following injection of allogeneic bone marrow (88). It also promotes the generation of allogeneic
hematopoietic chimeras and permanent transplantation
tolerance in the T-cell compartment when combined with
low-dose irradiation (33, 440).
Given these data, we developed a two-element protocol consisting of a pretransplant infusion of donor-specific
splenocytes enriched for resting B cells plus a course
of anti-CD154 MAb injections. We hypothesized that the
protocol would induce permanent allograft survival because the DST would initiate T-cell activation (signal 1),
but in the absence of costimulation (signal 2). Absence
of costimulation, which had been blocked by interference
with CD154-dependent coactivation signals, would induce
T-cell nonresponsiveness to the donor alloantigen in the
host (Fig. 3).
The theory predicted that the actual treatment period
could be short, needing to be applied only during the
immediate peritransplant period. The theory also predicted that the tolerance induced should be durable be-
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cause most or all alloreactive T cells should become unresponsive. This protocol was first tested in an islet allograft
model. Administration of a single DST and a 2-wk course
of anti-CD154 MAb (totaling 4 injections) induced permanent islet allograft survival in ú95% of chemically diabetic
hosts (297, 337). This result suggested that once tolerance
to the allograft was induced, further modulation of the
immune system may not be necessary.
We then extended the evaluation of this protocol to
determine if tolerance could be induced to skin allografts.
Because of the robust antigenicity of skin compared with
islets, it affords a much more challenging assay of transplantation tolerance. Our two-element protocol prolonged
survival of murine skin allografts. Median skin graft survival time was Ç50 days, and 20% of skin grafts survived
ú100 days (244).
Most recently, we have shown that the protocol can
be effective when applied to concordant rat to mouse
xenografts. In preliminary studies, combination therapy
with DST and anti-CD154 MAb significantly prolonged islet xenograft survival (240). Skin xenograft survival was
not prolonged (240). Subsequent refinement of the protocol has, however, lengthened skin xenograft survival significantly, to a median of 36 days (118).
These encouraging results have engendered intense
investigation of the two-element approach to induction of
transplantation tolerance using anti-CD154 MAb in combination with DST. An alternative approach using antiCD154 MAb in combination with simultaneous blockade
of CD28 and B7–1/2 costimulation is also being extensively investigated (see sect. IVA10C).
The promising outcomes achieved with DST and antiCD154 MAb have already generated talk of clinical trials.
The available data, however, leave unanswered at least
four important questions that should be addressed before
translation of this protocol to the clinic can be considered.
First, which component(s) of the host immune response
is being modulated, and can the tolerance-induction protocol be improved by targeting those components more
effectively? Second, what mechanism(s) is involved in the
induction and maintenance of the induced tolerance?
Third, how durable is the tolerant state? Can it be broken
easily by environmental perturbants? These questions can
be addressed in rodents where the model system can be
easily manipulated. Finally, will this two-element protocol
work in larger animals, specifically primates and humans?
Recent studies have provided insights, and in some cases
answers to most of these questions.
i) Affected components of the immune system. Extensive investigations have been carried out regarding the
components of the host response affected by this twoelement protocol, and these have led to its improvement.
The effects of anti-CD154 on the immune system per se
appear to be primarily directed at CD4/ T cells. Antibody
treatment can prevent the coactivation of helper/inducer
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CD4/ T cells and most of the effector and helper T- and
B-cell responses that are dependent on this cell subset (66,
103, 195). In allograft transplantation, this effect stems
primarily from the blockade of T cell-APC interaction via
CD40-CD154 and prevention of the subsequent upregulation of B7–1/2 costimulatory molecules on APC.
Other activities of anti-CD154 MAb that may be important in prevention of transplant rejection include effects
on NK cells (52), macrophages and dendritic cells (31, 247,
395), and endothelial cells (166, 234, 425). It has also been
shown that activated platelets express CD154 (148). The
role of rapid upregulation of CD154 on activated platelets
leading to endothelial cell activation has been shown to
occur in vitro and in vivo. The ability of anti-CD154 MAb to
block the coactivation activity of platelet-expressed CD154
on endothelial cells may be responsible, in part, for nonantigen-specific anti-inflammatory effects that are observed after
administration of anti-CD154 MAb (148).
Refinement of the protocol has yielded exciting information on the mechanism(s) involved and the durability
and stability of the tolerance that is induced. Cell composition of the DST has shown that small B cells are sufficient, but not required, for tolerance induction. Administration of whole spleen cell preparations is efficacious
(244), as is administration of spleen cells from B-lymphocyte knockout mice. T cells are not required in the donor
transfusion, because administration of spleen cell preparations from scid mice also induces tolerance in combination with anti-CD154 MAb. Finally, cell fractions enriched
for dendritic cells can function as the cell population as
the DST in combination with anti-CD154 MAb (229, 242a,
440). We conclude that, in combination with anti-CD154
MAb, a broad range of cell types can be used for the DST
component of our two-element protocol.
Experiments that modify the host immune response
have also yielded exciting insights into the basis for the
late failure of skin allografts following tolerance induction
using our two-element protocol. Thymectomy of the host
before starting the protocol results in permanent skin allograft survival in ú95% of recipients (243), an outcome
similar to that achieved in euthymic mice given islet allografts (297). These data suggest that the short-term treatment protocol induces tolerance in the preexisting T-cell
population but fails to induce tolerance in thymic emigrant populations that emerge later. This interpretation
predicts that modifications of the protocol that either periodically tolerize new thymic emigrants or prevent their
emergence from the thymus will enhance the durability
of induced graft tolerance.
ii) Mechanism. Recent experiments have also provided some insight into the mechanism(s) involved in the
induction and maintenance of tolerance. The role of CD4/
cells in both the induction and maintenance phases of the
graft-host interaction is now clear. Administration of antiCD4 MAb but not anti-CD8 MAb before starting the two-
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element protocol abrogates tolerance induction (243).
This result contrasts sharply with previous reports that
graft survival can be prolonged using only anti-CD4 MAb
(see sect. IVA6A). Our result suggests that an active process, mediated by CD4/ T cells, is critical for tolerance
induction by the two-element protocol. Furthermore, administration of depleting anti-CD4 MAb to mice that have
had intact skin grafts for long periods of time (ú100 days)
results in rapid graft rejection (243).
These effects could be mediated by the elimination
of CD4/ suppressor cells or by alteration of the cytokine
profile of the remaining cells, i.e., immune deviation. However, DST and anti-CD154 MAb readily induce tolerance
in IL-4 knockout mice, as well as in normal and thymectomized mice that have been treated continuously with antiIL-4 MAb, a Th2-type cytokine.
Tolerance cannot be induced by the two-element protocol in mice treated with anti-IFN-g or in IFN-g knockout
mice, hosts strongly biased toward Th2-type immune responses. These data suggest that if active suppression
is responsible for tolerance induction, it does not occur
through the mechanism of immune deviation (243).
Finally, CD28 and B7–1/2 interaction also appears to
play a critical role during the early phases of tolerance
induction when our protocol is applied. Administration of
anti-CTLA4 MAb prevents the induction of tolerance
(243). This observation suggests that interaction of CDTL4
with its ligands B7–1 and B7–2 is essential in the tolerance induction process. This last result contrasts sharply
with reports of investigations on the effect of combination
therapy consisting of anti-CD154 MAb and CTLA4-Ig. Administration of both reagents reportedly induces tolerance
to skin and heart allografts in mice even in the absence
of DST (201).
iii) Induction and maintenance phases. Taken together, these observations have led to the hypothesis that
the induction of tolerance using DST plus anti-CD154 MAb
involves at least two distinct critical stages or phases (see
Table 1). Phase 1 is the induction phase. This occurs during administration of the DST and the anti-CD154 MAb.
Phase 1 requires CD4/ T-cell activation, depends on the
interaction of CTLA4 with its ligands B7–1 and B7–2, and
requires IFN-g.
The second clearly delineated phase involves the
maintenance of tolerance in recipients with long-term intact grafts. This phase is also dependent on the presence
of CD4/, presumably suppressor T cells. Our hypothesis
predicts that the relative balance of CD4/ suppressor cells
with alloreactive recent thymic emigrants ultimately determines the long-term fate of the graft.
The ‘‘two-phase’’ or ‘‘two-stage’’ concept of tolerance
induction predicts that the first phase, induction, may be
relatively unstable. It appears to be dependent on the
administration of DST and the continued presence of antiCD154 MAb. The induction phase may easily be broken
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1. Phases of tolerance induction by donor-specific transfusion and anti-CD154 monoclonal antibody
Phase
Induction
Treatments
Immunologic events
Tolerance
Transplantation
Transition
Transfusion of alloantigen;
anti-CD154 MAb begins
IFN-g required; CD4/ T
cells required; CTLA4
ligation required
Surgery; anti-CD154 MAb
continues
Second exposure to
alloantigen; surgeryinduced inflammation;
graft antigenicity:
islets low, skin high
‘‘Tolerization’’ of preexisting
peripheral T cells begins
‘‘Tolerization’’ of
preexisting peripheral
T cells continues;
induction of CD4/
suppressor cells
Permanence
Anti-CD154 MAb ends
No treatments
Graft susceptible to rejection
due to alloreactive recent
thymic emigrants; in vitro
graft alloreactivity
demonstrable; CD4/ T
cells required; graft
susceptible to rejection
due to environmental
perturbants
Metastable equilibrium
between ‘‘untolerized’’ new
alloreactive thymic
emigrants and CD4/
suppressor cells
CD4/ T cells required; minimal
in vitro graft alloreactivity
demonstrable
Recognition of graft as self
MAb, monoclonal antibody; IFN-g, interferon-g.
by introduction of environmental perturbants while antiCD154 MAb is still being administered. This inference is
supported by our observations 1) that altering the timing
of the DST or anti-CD154 MAb relative to graft placement
influences graft survival and 2) that extended administration of anti-CD154 MAb is associated with prolonged skin
allograft survival (242). Our hypothesis also predicts that
once tolerance is induced, it is relatively stable. This is
evidenced by the long-term survival of both islet and skin
grafts that have not undergone acute rejection during the
induction phase. Our concept of the stages of allotolerance induction that follow treatment with DST and antiCD154 MAb is depicted schematically in Figure 4.
iv) Durability. We hypothesize that the durability of
transplantation tolerance may depend on events that occur during the transition from the induction to maintenance phases of the host response (193). We propose that
there may exist a third ‘‘metastable’’ phase of tolerance.
The metastability of this phase would explain the loss of
grafts that are intact during the actual treatment and escape acute rejection, but are nonetheless eventually rejected. We propose that the metastable phase is dynamic,
of varying duration, and dependent on active immune responses. Conceptually, it may in part depend on either 1)
the relative balance of suppressor and alloreactive effector cells that remain after the induction protocol is
complete or 2) the microenvironmental cytokine milieu
in the graft or the systemic circulation of the host. The
ability to transit the metastable phase to the long-term
maintenance phase may also depend on 1) the degree of
inflammation induced in the host due to surgical manipulation during transplantation and 2) the resilience of the
graft as it recovers from the surgical and inflammatory
trauma of transplantation.
B) COMBINATION OF CTLA4-IG AND DST. CTLA4-Ig has as
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strong affinity for, and ability to block, the interaction
of the B7–1/2 costimulatory molecule with CD28. These
characteristics predicted it to be a potent immunoregulatory of immune responses important in allograft rejection.
It was observed in early studies of CTLA4-Ig fusion protein
in transplantation that the CTLA4-Ig immunomodulatory
agent promoted graft survival more efficiently if combined
with exposure to alloantigen by DST (345, 350). Administration of CTLA4-Ig by itself was insufficient to prevent
heart allograft rejection, but when combined with DST,
vascularized heart allograft survival was prolonged significantly (218).
Administration of CTLA4-Ig plus bone marrow also
prolonged the survival of cardiac allografts in mice receiving a completely MHC-mismatched graft, but the treatment did not prolong skin allograft survival (301). Surprisingly, the cytokines detectable in graft recipients that
were treated with CTLA4-Ig and DST were identical to
those detected in unmanipulated control graft recipients.
The expression of granzyme, perforin, Fas, and FasL
mRNA was also similar in treated and control graft recipients. The experiments also revealed that Th2-type cytokines were readily detectable in the hosts and that CTLA4Ig appeared specifically to inhibit the Th1-type T-cell immune response. The data suggest that graft survival in
animals treated with CTLA4-Ig plus DST may involve multiple mechanisms, including microchimerism, anergy, and
immune deviation (301).
C) COMBINATION OF CTLA4-IG AND ANTI-CD154 ANTIBODY.
A second two-element protocol consisting of anti-CD154
MAb and CTLA4-Ig has also been evaluated for transplantation tolerance induction (201). This approach is
based on the hypothesis that anti-CD154 MAb should prevent interaction with CD40 and coactivation, while at the
same time CTLA4-Ig should prevent costimulation of any
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125
FIG. 4. Depicted in schematic form is our concept of
stages of allotolerance induction that occur during and
after treatment with donor-specific transfusion (DST) and
anti-CD154 monoclonal antibody (MAb). During treatment,
suppressor cell populations are induced, and alloreactive
T-cell activity begins to decline. When graft is actually
transplanted at conclusion of this ‘‘induction’’ phase, alloreactive cell activity declines greatly. After transplantation,
there occurs a transition period of variable duration during
which time graft is ‘‘metastable.’’ This is depicted as a
balance between alloreactive (A) and suppressor (CD4)
cells that may be disequilibrated in either direction. If a
balance progressively favoring suppressor cells is maintained through transition period, then graft survival (depicted here as a mouse skin graft typical of those on which
this concept is based) becomes permanent. IFN-g, interferon-g.
alloreactive T cells that were either preactivated or escaped the effects of CD40-CD154 blockade. The combination of these two reagents prolongs the survival of fully
allogeneic skin and vascularized heart allografts. In skin
graft studies, it was shown that both reagents were required; neither was effective by itself. In vascularized
heart allografts, anti-CD154 MAb by itself was able to prolong graft survival (200). Combined treatment with antiCD154 MAb and CTLA4-Ig was also able to prevent the
chronic rejection commonly associated with mouse aortic
allografts (399). The mechanism(s) directly responsible
for the tolerance induced by this approach have not been
identified but are likely to involve both redundant
blocking of both coactivation and costimulation as well
as additional factors (351).
the acute rejection of allografts and facilitate their longterm survival. Any transplant protocol in humans that excludes generalized immunosuppression, however, must
be robust and durable as documented in primate studies.
Unfortunately, the application of tolerance induction protocols pioneered in rodents to larger animals, specifically
primates, has proven difficult.
As in rodents, there have been two general experimental approaches to the induction of transplantation tolerance in primates. The first is the use of immunomodulatory reagents in the absence of general immunosuppression; the second is the use of general immunosuppression
with or without immunomodulatory reagents.
1. Anti-CD154 MAb and DST in large animal models
D) CTLA4-IG PLUS OTHER IMMUNOMODULATORY OR IMMUNOSUPPRESSIVE AGENTS. Experiments featuring the combination of CTLA4-Ig with other drugs have been undertaken in part because of the belief that utilization of any
new agent in clinical transplantation will almost certainly
require its combination with currently used agents. Accordingly, CTLA4-Ig has been tested in combination with
cyclosporine (39) and tacrolimus, two conventional immunosuppressive agents (136). Although prolongation of
graft survival was observed, graft rejection did eventually
occur in all cases.
Finally, CTLA4-Ig has been combined with the promising technique of intrathymic injection of alloantigen
(382). Again, graft survival in this experiment was prolonged but not permanent.
B. Methods Successful in Large Animals and
Primates
Data from rodent experiments suggest that there are
multiple avenues for immunomodulation that may prevent
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Among species, CD40 and CD154, as well as CD28
and B7–1/2, are strongly conserved. The coactivation and
costimulation pathways mediated by these molecules appear to be important in the regulation of immune responses in rodents, larger mammals, primates, and humans (66, 103, 195). The possibility therefore exists that
the basic paradigm developed in murine models may be
extendable to primates and perhaps even to humans. Preliminary indications suggest that this may, in fact, be the
case.
In studies of primates, two-element therapy composed of DST and anti-CD154 MAb prolongs kidney allograft survival (336). Administration of anti-CD154 MAb,
with or without the addition of CTLA4-Ig to block CD28
and B7–1/2 interactions, also can prolong kidney allografts in primates (see sects. IVA9 and IVA10C).
The preliminary results in rodents and primates now
suggest that clinical trials using the two-element protocol
may be feasible. The development of anti-human CD154
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ROSSINI, GREINER, AND MORDES
MAb, and the humanization of these MAb (104, 171),
should permit this approach to be extended to the clinic
in the near future.
2. Anti-CD154 MAb and CTLA4-Ig in large
animal models
Several published reports on tolerance induction in
monkeys using immunomodulatory reagents without immunosuppression have employed CTLA4-Ig alone or with
anti-CD154 MAb (171, 215). Using CTLA4-Ig alone, two of
five monkeys with chemical diabetes that were treated
with CTLA4-Ig and transplanted with allogeneic islets became normoglycemic and remained free of diabetes for
30 and 50 days without additional treatment (215). In a
second study, rhesus monkeys were transplanted with allogeneic kidneys and given human CTLA4-Ig, humanized
anti-human CD154 MAb, or both reagents (171). In these
monkeys, either reagent alone prolonged graft survival to
20–98 days, and in two of the four monkeys treated with
both reagents, kidney allograft survival was ú150 days.
In the absence of continuous treatment however, episodes
of rejection occurred; in these instances, administration
of additional anti-CD154 MAb preserved graft function.
Other preliminary reports in primates describe prolonged survival of islet allografts in pancreatectomized
cynomologus monkeys, baboons, and rhesus monkeys
treated with anti-CD154 MAb alone (169, 212). In these
cases, prolonged graft survival required a brief induction
course of anti-CD154 MAb in the perioperative period and
additional monthly maintenance doses.
In all of these cases in which antibody alone was used
to induce transplantation tolerance, it will be of interest to
determine if passenger APC in the donated graft subserved the function of a DST.
These results, combined with our preliminary experience using the two-element protocol in monkeys, suggest
that immunomodulatory reagents targeted to the coactivation and costimulation molecules on T cells and APC have
the potential to induce transplantation tolerance in humans.
3. Other immunomodulatory approaches in large
animal models
Several other approaches have been employed using
various forms of generalized or specific immunosuppression. These include the use of the immunotoxin FN18CRM9, which is an anti-rhesus CD3 MAb (FN18) conjugated to the mutant diphtheria toxin protein CRM9 (271).
This reagent has been used to induce tolerance in monkeys to kidney (96) and skin (175) allografts in combination with intrathymic injection of donor lymphocytes. The
combined protocol appeared to downregulate antidonor
CTL activity in the kidney allograft recipients, whereas
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helper T-cell and B-cell function and reactivity to third
party allografts remained unaffected.
A more traditional approach has employed combinations of various immunosuppressive techniques for tolerance induction to kidney allografts in cynomologus monkeys (170a). The preparative regimen included various
combinations of whole body low-dose irradiation, antithymocyte globulin, thymic irradiation, splenectomy, and donor bone marrow infusion with or without a short course
of cyclosporine. The conclusion drawn from this study
was that long-term graft survival can be obtained using
combination immunosuppressive therapy, but the best
predictor of graft survival was the extent of chimerism
achieved.
These limited studies using only immunomodulatory
therapy or low-dose immunosuppressive regimens with
immunomodulatory agents have provided promising evidence that it will prove possible to induce transplantation
tolerance in primates. However, the mechanism(s) responsible for graft survival in these primate protocols remains unknown and will be difficult to analyze experimentally. The combination of rodent experimentation and extrapolation to the primate offers the most promising
approach to the development of optimal tolerance induction protocols with applicability to humans.
C. Evidence of Tolerance Induction in Humans
Because of the universal acceptance of immunosuppression in current clinical practice, there is little evidence to document the presence or absence of immunologic tolerance in human graft recipients. Among the few
available data are those reported by Starzl et al. (385).
Those data focus on human graft recipients who for various reasons discontinued immunosuppressive therapy but
nonetheless continued to retain their allograft (385).
Those data were interpreted to suggest that passenger
leukocytes migrate after organ transplantation and produce a microchimeric state that is essential, and in some
cases sufficient, for allograft maintenance. One other set
of observations is also consistent with the existence of a
tolerant state. These data are from human liver allograft
recipients and suggest that this tissue may have the ability
to produce a tolerant state based on the uniquely high
antigenicity of this organ (385).
V. CONTEMPORARY CLINICAL
ORGAN TRANSPLANTATION
A successful organ transplantation program must establish a set of outcome criteria that must be met and
must identify and overcome obstacles to meeting those
criteria. All criteria are, of course, based on the premise
that good donor tissue is available. Mundane but crucial
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methodologies must be perfected. These include organ
and tissue harvesting techniques, preservative solutions,
and preparative manipulation, and protocols unique for
each tissue or organ have been formulated.
A. Criteria for Successful Transplantation
Program
The first criterion is availability of organs or tissues
for transplantation. The recovery and distribution of human organs and tissues for transplantation has been organized nationally under a program titled UNOS (United
Network for Organ Sharing). This scientific registry reported in 1995 that its organ recipient waiting list had
grown to Ç38,000 individuals, and it is estimated that 9
persons die each day awaiting a human allograft. The
shortage of organs for transplantation continues to grow.
The second criterion is viability of the organ or tissue
to be transplanted. Each tissue or organ again has its own
unique requirements, but grafts can be grouped into two
general categories. One group includes vascularized organs that require surgical anastomosis of the recipient’s
vascular system. The second group includes nonvascularized tissues. These require transplantation into a site
where they can be bathed in tissue fluids that are adequate
to furnish nutrients and remove or dilute waste metabolites. The first group includes heart, kidney, liver, and
lung. The second group includes islets of Langerhans. This
dispersed tissue that can be implanted intraportally or
intraperitoneally where they survive in the absence of
surgical attachment to the vascular system.
The third criterion is functionality of the transplanted
organ or tissue. Simple survival of the transplant is obviously not the critical outcome variable. The transplanted
organ must replicate the function of the organ that it is
replacing.
The fourth criterion is application of appropriate harvesting techniques. Clearly, harvesting of solid organs requires different approaches than does harvesting of tissues like islets. All approaches have in common a minimization of ischemia time and the use of preservative
solutions, with each preservative solution tailored to the
particular organ or tissue. For example, to recover islets,
the pancreas must be perfused immediately with specific
preservative solutions such as Wisconsin’s solution. The
islets must then be dissociated from the pancreas within
hours of harvest, usually by collagenase digestion, cultured for several days, and if not transplanted at the end
of culture cryopreserved for transplantation in the future
(188, 189). For each organ or tissue, the optimal protocol
is detailed and idiosyncratic.
The fifth criterion is safety of the donor organ or
tissue. Safety preeminently focuses on bacterial and viral
infection of the donor host organ or tissue. Donors with
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bacterial septicemia may not be appropriate donors. Donors infected with hepatitis virus, human immunodeficiency virus, or other pathogenic viruses are not acceptable donors. All transplant programs screen for a number
of viruses and bacterial pathogens before use of the donor
tissue for transplantation, but in no cases can the surgeon
be completely ensured of the pathogen-free status of the
donor organ or tissue. The special issue of infected xenografts is considered in section VID.
B. Issues of Graft Placement
The site of transplantation may be critically important for the survival and function of a graft. For many
grafts, this requirement constrains choices for the site of
graft placement. The graft must be positioned to allow it
to perform the function of the organ or tissue being replaced. For vascularized grafts such as the heart, liver, or
lung, the graft must be an orthotopic graft, i.e., placed in
the normal position for that tissue or organ. Survival of the
graft in an unsuitable anatomic location is of no benefit to
the recipient. In contrast, kidneys and insulin-secreting
islets can be transplanted heterotopically, i.e., in a site
different from the natural location. Implantation of islets
into the liver or peritoneum rather than the pancreas not
only achieves physiological function but may also enhance the chances of graft survival.
C. Immunosuppression
Immunosuppression is currently required for the survival of all but autologous and some syngeneic grafts.
Although there are many forms of immunosuppression,
including general and targeted forms, there is at present
no immunosuppressive agent that is completely safe and
free of toxic side effects. Immunosuppressive drugs are
the current method of choice, but their use restricts transplantation of tissues or organs to life-threatening disorders. An optimal immunosuppressive regimen employed
to permit graft acceptance needs to be safe and free of
adverse effects to the recipient. The extent and duration
of immunosuppression will have a significant impact on
the incidence of infections and tumors experienced by
the recipient.
VI. TRANSPLANTATION AFTER TOLERANCE
The focus of this review has been improvement in
the safety and efficacy of transplantation by exploiting
new insights into immunologic tolerance. The goal is to
reduce or eliminate our current dependence on immunosuppressive drugs. It is not clear that tolerance can be
induced, and translation of the theories and methods we
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have reviewed to clinical medicine seems a question of
if, not when. We conclude with a brief consideration of
some issues that must be confronted as the implementation of tolerance-based therapy proceeds.
A. Demand for Transplantation Services
Therapy for patients with disorders that were once
rapidly fatal have improved dramatically. Hemodialysis
for renal failure, afterload reduction for heart failure, and
intensive insulin therapy for diabetes (pancreatic islet cell
failure) are now routine. As brilliantly successful as these
therapies are, however, they are temporary, not curative.
As it becomes possible to consider transplantation for
individuals who would have been marginal candidates in
the immunosuppression era, demand and expectations
will certainly rise.
1. Organ transplantation is physiologically curative
The availability of organ transplants in the absence
of immunosuppression will highlight the physiological advantages of organ replacement over current therapy. One
example is in the area of diabetes. Intensive insulin therapy can retard, but not preclude, the life-threatening complications of hyperglycemia. The physiological cost (in
terms of hypo- and hyperglycemia, for example) and the
financial cost are both high, but in the immunosuppression era, most persons with diabetes take a wait-and-see
attitude to islet transplantation. This may change dramatically in an era of tolerance-based therapy for at least three
reasons. 1) Long-term safety will be enhanced by the elimination of chronic immunosuppression. 2) Restoration of
total islet functionality (e.g., physiological secretion of
insulin, proinsulin, C-peptide, glucagon, and somatostatin) is more likely to prevent complications than insulin
injection (152). Finally, long-term functionality of transplanted islets may also be able to reverse diabetic complications already present at the time of grafting (99).
Volume 79
sues of graft survival and graft function. Very little is as
yet known about possible unforeseen consequences of
inducing tolerance. Ideally, tolerance would be induced
quite specifically to one tissue from one donor, leaving
the host immune system’s native capabilities to respond
to danger unimpaired. This degree of specificity may not
necessarily be achieved, however, and compromises in
the ability of a recipient in the areas of infection defense
or immune surveillance must be considered.
2. Durability
The durability of transplantation tolerance has been
a recurring theme in this review. It is not yet known,
however, what will be required to maintain graft tolerance
for a lifetime or what factors might break tolerance. It
remains, for example, to be proven if tolerized grafts will
continue to survive if the host is forced to mount an immune response to infection or trauma.
3. Chronic rejection
Another major point that confronts any transplant
program is the prevention of chronic rejection. The majority of kidney transplants, with a modern day initial acceptance rate of ú90%, inevitably fail due to the development
of chronic rejection and the loss of function. The pathophysiology of chronic rejection is poorly understood, and
current immunosuppressive therapies often fail to reverse
chronic rejection, eventually leading to graft failure.
4. Recurrence of disease
It is now recognized that the cure of disease by successful organ transplantation, even with the accompanying risks and side effects of immunosuppression, provides substantial psychological benefit to patients. If tolerance-based transplantation reduces the risk of toxicity
and the attendant fear of the procedure, wider recognition
of the restoration of spiritual health and wider perception
of bodily integrity are likely to increase demands on transplantation centers.
Most organs requiring replacement have been lost
due to trauma, ischemia, congenital malformation, abnormal metabolic states, or other nonimmune processes. Others, however, have been lost due to autoimmune disease.
Examples include lupus nephritis, autoimmune cardiomyopathy, and autoimmune diabetes. In these cases, the autoimmune disease may affect a healthy graft. This is
known from studies of monozygotic twins discordant for
diabetes. Syngeneic segmental pancreas transplantation
from a healthy to a diabetic sibling (which requires no
immunosuppression) fails due to recurrence of the original disease in the healthy graft (401). How tolerance-based
transplantation will function for patients with underlying
autoimmune diatheses is not known. Combination therapies directed at the autoimmunity and at alloantigenicity
have been suggested, but how they would interact is also
unknown.
B. Potential Pitfalls
C. Issues of Donor Tissue and Organ Availability
1. Specificity of induced tolerance
As tolerance-based transplantation becomes a reality,
the inadequate supply of donor tissue will become an
ever more serious problem. Cadaveric donor organs are
2. Psychological advantages of organ transplantation
Experimental procedures designed to evaluate transplantation tolerance induction of necessity focuses on is-
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sufficient for only Ç10% of total need at the present time.
The gap between requests for donor tissues and their
availability continues to grow. One possible source that
remains underutilized is human fetal tissues, but ethical
and legal barriers to their use may be insurmountable.
A second approach is the development of bioengineered
tissues. Bioengineered tissues could take many forms: organs from transgenic and knockout animals, transfected
allogeneic cell lines designed to eliminate antigenicity
while preserving (or adding) function, and, most speculatively, tissues grown in vitro from pluripotent donor cells
(neogenesis). These strategies are all in their infancy and
clinically unproven.
2.
3.
4.
5.
6.
D. Special Case of Xenografts
7.
We have devoted considerable attention in this review to the induction of tolerance to xenografts, focusing
on the special immunologic characteristics (e.g., indirect
antigen presentation) that distinguish xeno- from allografts. The potential use of xenografts raises special ethical and psychological issues for physicians and recipients
(67). More importantly, it raises the specter of introducing
new diseases into the human population. From an infectious disease standpoint, the issue is exceedingly complex. The specter of xenozonotic epidemics has been
raised and has become a focus of concern (17).
8.
9.
10.
11.
12.
E. Conclusion
The advances in transplantation biology that have
occurred in recent decades are stunning, if not miraculous. Through the use of immunosuppressive drugs, transplantation has become a widespread reality. Potentially
safer and more efficacious transplantation methods based
on tolerance induction are already a real possibility. One
wonders if humans of the future will actually embody the
miracle of transplantation to the extent depicted by Fra
Angelico in his painting of the patient of Cosmas and
Damian.
We thank Dr. Jeffrey Stoff for critical review of the manuscript.
This work was supported in part by National Institute of
Diabetes and Digestive and Kidney Diseases (NIDDK) Grants
DK-25306 (to A. A. Rossini), DK-41235 (to J. P. Mordes), and DK36024 (to D. L. Greiner); by a grant from the Iacocca Foundation;
and by Program Project Grant DK-53006, jointly funded by
NIDDK and the Juvenile Diabetes Association International (to
A. A. Rossini).
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