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TRANSPLANTATION IMMUNOLOGY.
Hilu Rashad, MD Student.
Introduction
⚫ The field of organ transplantation has made remarkable
progress in a short period of time.
⚫ Transplantation has evolved to become the treatment of
choice for end-stage organ failure resulting from almost any
of a wide variety of causes.
⚫ Transplantation of the skin, kidney, liver, pancreas,
intestine, heart, and lungs has now become common in all
parts of the world.
Definition of Transplantation
⚫ Implantation of “non-self” tissue into the body
⚫ The process of taking cells, tissues, or organs called a graft
(transplant), from one part or individual and placing them into
another (usually different individual).
⚫ donor: the individual who provides the graft.
⚫ recipient or host: the individual who receives the graft.
Methods of Transplantation
⚫ Autologous graft (autograft) –from one site to another one in
the same individual (e.g., the use of a patient’s own skin to
cover third-degree burns or a saphenous vein femoropopliteal
graft)
⚫ Isogenic (isograft) – between genetically identical individuals of
the same species (e.g., kidney transplant between identical twins).
⚫ Allogeneic (allograft or homograft) -transplantation of tissue
between genetically non identical members of the same species
(e.g., cadaver , live donor solid organ transplant )
⚫ Xenogeneic (xenograft) –transplantation of tissue between
members of different species (e.g., baboon kidney into a
human).
Transplant Antigens
⚫ The main antigens involved in triggering rejection are
coded for by a group of genes known as the major
histocompatibility complex (MHC).
⚫ In humans, the MHC complex is known as the human
leukocyte antigen (HLA) system. It comprises a series of
genes located on short arm of chromosome 6.
Major Histocompatibility Antigens
⚫ It includes 3 regions: class Ia (loci A, B, C)
class Ib (loci E, F, G, H), class II (loci DR, DQ, DP) and
class III
⚫ Histocompatibility antigens are cell surface expressed on all
cells (class I) and on APC, B cells, monocytes/macrophages
(class II)
⚫ They are targets for rejection
⚫ They are inherited from both parents as MHC haplotypes
and are co-dominantly expressed
⚫ HLA
molecules
can initiate rejection
damage, via humoral or cellular mechanisms:
and
graft
Humoral rejection mediated by recepient's antibodies. (e.g.
blood transfusion, previous transplant, or pregnancy)
Cellular rejection is the more common type of rejection
after organ transplants. Mediated by T lymphocytes, it
results from their activation and proliferation after
exposure to donor MHC
MECHANISMS OF REJECTION
Rules of Transplantation
Recognition of Alloantigens
⚫ Direct Presentation
A MHC molecule is displayed by antigen-presenting cells (APCs)
in the graft and recognized by recipient T cells without a need for
host APCs.
⚫ Indirect Presentation
Donor MHC molecules are captured and processed by recipient
APCs and then presented to T cells
Direct and Indirect Recognition
Figure 16-3
Difference between Direct Recognition and
Indirect Recognition
23
Effector Functions of Alloreactive T Cells
⚫ Alloreactive CD4+ and CD8+ T cells that are activated by
graft alloantigens cause rejection by distinct mechanisms.
⚫ The CD4+ helper T cells differentiate into cytokine
producing effector cells that damage grafts by cytokine
mediated inflammation, similar to a delayed-type
hypersensitivity (DTH) reaction
⚫ Alloreactive CD8+ T cells differentiate into cytotoxic T
lymphocytes (CTLs), which kill nucleated cells in the graft
that express the allogeneic class I MHC molecules.
⚫ CTLs also secrete inflammatory cytokines, which can
contribute to graft damage.
Activation of Alloreactive B Cells and
Production of Alloantibodies
⚫ Most high-affinity alloantibodies are produced by helper T cell–
dependent activation of alloreactive B cells, much like
antibodies against other protein antigens
⚫ The antigens most frequently recognized by alloantibodies in
graft rejection are donor HLA molecules,including both class I
and class II MHC proteins.
⚫ The naive B lymphocytes recognize foreign MHC molecules,
internalize and process these proteins, and present peptides
derived from them to helper T cells Thus, producing
Alloantibodies which cause allograft rejection.
TYPES OF REJECTION
⚫ Hyperacute rejection is characterized by thrombotic occlusion
of the graft vasculature that begins within minutes to hours
after host blood vessels are anastomosed to graft vessels and is
mediated by preexisting antibodies in the host circulation that
bind to donor endothelial antigens
⚫ Acute rejection is a process of injury to the graft
parenchyma and blood vessels mediated by alloreactive T
cells and antibodies .
TYPES OF REJECTION
⚫ Chronic rejection
various mechanisms: cell-mediated, deposition of
antibodies or antigen antibody complexes with subsequent
obliteration of blood vessels and interstitial fibrosis
⚫ A dominant lesion of chronic rejection in vascularized grafts
is arterial occlusion as a result of the proliferation of
intimal smooth muscle cells, and the grafts fail because of
the ischemic damage.
Rate of rejection: The rate of rejection depends on the type underlying
effector mechanisms:
Type of rejection
Time taken
cause
Hyperacute
Min-hours
Anti-donor Ab and
complement
Accelerated
Days
Reactivation of T cells
Acute
Days- weeks
Primary activation of T
cells
Chronic
Months- Years
Unclear
GRAFT VERSUS HOST DISEASE (GVH)
⚫ Graft mounts an immune response against the antigens of host .
⚫ Is common complication in recipients of bone marrow
transplants
⚫ Is due to the presence of alloreactive T cells in the graft
⚫
It results in severe tissue damage, particularly to the skin and
intestine
⚫ It may be avoided by careful typing, removal of mature T cells
from the graft and by immunosuppressive drugs
⚫ It is manifested by marked rise of several cytokines in patient’s
serum (IFN-, TNF, IL-1, IL-2, IL-4)
RISK FACTORS IN FORMATION OF GVH
Acute GVH
Chronic GVH
⚫ Previous pregnancies in
⚫ Aging of donor and recipient
female donor
⚫ High T cell number in
marrow
⚫ HLA disparity
⚫ Transplant from female to
male
⚫ Low immunosuppression
⚫ Herpes virus infection
⚫ Donor’s leukocyte
transfusion
⚫ Previous acute GVH
⚫ High dosage radiation
⚫ Transplant from female to
man
⚫ HLA disparity
Prevention of transplant rejection
⚫ Tissue Typing
 ABO and Rh blood typing
 Cross matching (Preformed antibodies)
 HLA typing
⚫ Immunosuppressive Therapy
⚫ The pretransplant laboratory evaluation & immunization
⚫ Pre/post transplant prophylaxis
Most Common Transplantation
-Blood Transfusion-
Transfuse
Not transfused
Methods of HLA typing
⚫ Microcytotoxicity test
⚫ Molecular methods -RFLP/PCR
⚫ Tissue matching- Mixed lymphocyte reaction( MLR)
Mixed lymphocyte reaction (MLR).
⚫ The response of alloreactive T cells to foreign MHC
molecules can be analyzed in an in vitro reaction called
the mixed lymphocyte reaction (MLR).
⚫ MLR is a predictive test of T cell–mediated graft rejection.
Pretransplant Evaluation
⚫ The pretransplant laboratory evaluation
Tests to obtain in all transplant
candidates
Serologies
Other tests
Cytomegalovirus
Urinalysis
Herpes simplex virus
Urine culture
Varicella-zoster virus
Tuberculin skin test or
Epstein Barr virus
Chest radiograph
Human immunodeficiency virus
Sputum stains and cultures
Hepatitis B virus: HBsAg, HBsAb,
HBcAb
Hepatitis C virus
Treponema pallidum
Toxoplasma gondii (in heart transplant
candidates)
For bacteria, mycobacteria, and fungi (in
lung transplant candidates)
IMMUNISATION
⚫ Hepatitis B : Routine vaccine schedule recommended
prior to transplant
⚫ If no tetanus booster in the past 10 years, then it
should be administered.
⚫ Pneumovax should be administered before
transplantation and repeated once 3-5 years after initial
vaccination.
• N. Meningitis vaccine: Recommended for patients
 Members of the military
 Travellers to high risk areas
 Properdin deficient
 Terminal complement component deficient
 Those with functional or anatomic asplenia
• Rabies: Not routinely administered. Recommended
for exposures or potential exposure
• Varicella Zoster Vaccine : indicated for persons ≥ 60
years
• Patients listed for organ transplantation should undergo tuberculin
skin testing.
• Baseline chest radiographs should be obtained for anyone with
epidemiologic history suggestive of possible exposure.
•
Pretransplant anti-tuberculous prophylaxis or therapy for following
specific indications:
 Tuberculin reactivity of ≥ 5 mm before transplantation
 History of tuberculin reactivity without adequate prophylaxis
 Recent conversion of tuberculin skin test to positive
 Radiographic evidence of old TB. A chest CT scan is performed to look for
disseminated disease and to serve as a baseline study.
 History of inadequately treated TB
 Close contact with an individual with active pulmonary TB
 Receipt of an allograft from a donor with a history of untreated TB
Common Types of Infecting Microbial Agents after Transplantation
Bacteria
Viruses
Gram-negative bacteria
Enteric bacteria (Escherichia
coli, other Enterobacteriaceae)
Pseudomonas
Acinetobacter
Serratia
Bacteroides and other
anaerobes
Legionella
Gram-positive aerobes
Staphylococcus aureus
(MRSA)
Staphylococcus epidermidis
Streptococcus
Enterococcus (VRE)
Pneumococcus
Listeria monocytogenes
Nocardia
Gram-negative coccobacilli
Haemophilus influenzae
Herpes simplex virus (HSV)
Cytomegalovirus (CMV)
Varicella-zoster virus
Epstein-Barr virus (EBV)
Human herpesvirus-6
Human herpesvirus-8
Human immunodeficiency virus 1 (HIV1)
Adenovirus
Rotavirus
Respiratory syncytial virus
Influenza A and B viruses
Para influenza viruses
West Nile virus
Hepatitis B virus
Hepatitis C virus
Polyomavirus
Papillomavirus
Parvovirus
Common Types of Infecting Microbial Agents after Transplantation
Fungi
Mycoplasmas
Candida spp.
Aspergillus spp.
Cryptococcus
Agents of mucormycoses
Histoplasma capsulatum
Coccidioides immitis
Pneumocystis jirovecii
Mycoplasma hominis
Ehrlichia
Ehrlichia chafeensis
Anaplasma phagocytophilum
Protozoa and Parasites
Toxoplasma gondii
Trypanosoma cruzi
Strongyloides stercoralis
Timetable of infection after solid (renal) transplantation. HSV, CMV, EBV, VZV, Papova,
TB.
Prevention of infection post-transplant Marty and RubinTransplant International 19 (2006) 2–11
Antimicrobial Prophylactic Regimens in Transplantation
Pathogen
Protozoa
Toxoplasmosis
,Pyrimethamine
Viral
Herpes simplex
Cytomegalovirus
,Foscarnet
Influenza
Fungal
Candida
Aspergillus
Pneumocystis
Bacterial
Wound infection
Urinary tract infection
Neutropenic infection
Tuberculosis
Prophylactic Agents
Trimethoprim-sulfamethoxazole
Acyclovir
Ganciclovir, Acyclovir ,Immunoglobulin
Amantadine, Rimantadine, Oesiltamivir
Fluconazole, Nystatin, Clotrimazole
Voriconazole
Amphotericin B, Liposomal amphotericin
TMP-SMX, Dapsone,Inhaled pentamadine
Variable
TMP-SMX
Quinolones
Isoniazid
Immunosuppressive Therapy
• The calcineurin inhibitors cyclosporine and FK506 (tacrolimus)
inhibit transcription of certain genes in T cells, most notably
those encoding cytokines such as IL-2.
• Rapamycin (sirolimus) inhibits growth factor–mediated T cell
proliferation
• Antimetabolites are metabolic toxins that kill proliferating T cells
eg. mycophenolate mofetil(MMF).
•
Azathioprine, Cyclophosphamide
• Block the proliferation of lymphocytes
• Anti-inflammatory agents
• Corticosteroids----Block the synthesis and secretion of cytokines
PERSPECTIVES OF XENOGENEIC GRAFTS
• Potential advantage due to larger accessibility of animal organs
• Monkeys are apparently the most suitable donors, but
dangerous because of potential risk of retrovirus transfer within
graft
• Pigs are now considered because of similar sizes of organs and
erythrocytes to human ones
• The major obstacle – presence in man (1%) of natural
antibodies vs. Gal (galactose--1,3-galactose) causing
hyperacute rejection
SUMMARY
• Major histocompatibility complex is the main antigens
involved in triggering transplant rejection .
• HLA molecules initiates rejection and graft damage, via
humoral or cellular mechanisms.
•
Donor alloantigens are presented by APCs to T
lymphocytes of recipient by direct/ indirect methods


SUMMARY
•
Immature dendritic cells within the graft carry donor
antigens from the transplanted organ to the recipient’s
draining lymph nodes ; during their journey, these antigens
mature into APCs
• The APCs then home to lymphoid organs
• Here they activate the recipient’s T cells.
• These T cells differentiate into various subgroups and
return to the graft and destroy the transplanted organ
SUMMARY
• Rejection can be acute , hyperacute and chronic.
• GVHD - graft mounts an immune response against the
antigens of host .
• Transplant rejection can be prevented by tissue typing &
proper screening of the patients for infections.
• Every transplant patient should get appropriate
immunization & prophylactic drugs.
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