Dr. Fadwah Al-Ghalib
Diagnostic Immunology
3rd year
TRANSPLANTATION & REJECTION
Objectives:
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To know the benefit of transplantation in clinical medicine
to know the immunological mechanism of rejection
To know the immunological and physiological barriers to transplantation
to know the roles of T cells and MHC molecules in rejection
To understand the methods of rejection prevention
To know and understand the laboratory tests for tissue compatibility
---------------------------------------------------------------------------------------------Transplantation is important because:
a. Its impact on understand immunological processes
b. Its application in the development of clinical transplantation
Mouse skin-graft rejection study has led to:
1. The discovery of the MHC molecules
2. Better understanding of T cell physiology and function
3. The development and use of immunomodulatory drugs.
Barriers to Transplantation:
Described in terms of genetic disparity between donor and recipient.
Graft can be classified into:
o Autografts: ( from one part of the body to another).
o Isograft: (between genetically identical individuals, monozygote twins)
o Allograft: (Between genetically different individuals from the same species)
o Xenogeneic: ( Between members of different species, but is rapidly rejected
by IgM Abs or by cell-mediatedrejection).
Applications of clinical transplnats : organs and tissues are transplanted to treat
various conditions, each type of transplant has its own particular medical and surgical
difficulties.
Organ transplant
Examples of disease
Kidney
End-stage renal failure
Heart
Terminal cardiac failure
Liver
Cirrhosis, cancer
Cornea
Dystrophy, Keratitis
Pancreas or islets
diabetes
Bone marrow
Immunodeficiency, leukaemia
Small bowel
Cancer
Skin
burns
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Dr. Fadwah Al-Ghalib
Diagnostic Immunology
3rd year
Histocompatibility Ags:
1. They are responsible for rejection
2. There are more than 30 MHC gene loci, and they cause rejection at
different rates.
3. They present antigens to T cells (called HLA {human leukocytes
antigen}.system.
4. Cellular constituents are called minor histocompatibility antigens,
causes weaker rejection responses.
5. Combination of several minor antigens can elicit strong rejection
responses.
-MHC haplotypes are inherited from both parents.
- Inherited MHC genes are all expressed on the cell surface
Class I expressed on most nucleated cells.
Class II are restricted to: APC (dendritic cells and macrophages) and B cells.
-MHC molecules re expressed on transplanted tissues and induced by cytokines (IFN, TNF).
The Laws Of Transplantation:
a. Foreign MHC molecules can directly activate T cells
b. Host-Versus-graft responses cause transplant rejection: happens when
the graft carries any antigen that aren't present in the recipient.
c. Graft-versus host reactions: results when donor lymphocytes attack the
graft recipient.
The Role Of T Lymphocytes in Rejection:
2) T cells are pivotal in graft rejection:
Rodents born without a thymus (nude) have no mature T cells and cause no
transplant rejection.
2- Irradiation to remove existing mature T cells leads to inability to reject
transplant.
3- ability to restore graft rejection in these nude rodents is by injection of T cells
from a normal animal of the same strain
4- T-helper (TH) cells (CD4) and lymphokines are involved in rejection.
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Dr. Fadwah Al-Ghalib
Diagnostic Immunology
3rd year
(such as IL-2 which is required for activation of TC cells, and IFN  which
induces MHC expression, increases APC activity, activates Macrophage,in turn
release TNF  an important mediator for graft rejection.) IL-4 , -5 and -6 are
required for B-cell activation, leading to the production of anti-graft abs.(fig:1.1)
Presentation of graft Antigens
1. High density of graft MHC molecules react weakly with TCR and generates signal
for T cell activation.
2. Graft MHC molecules can present the graft's own peptides including peptides from
both major/minor MHC molecules
3. Graft MHC can present processed antigen of host molecules causing lack of host
tolerance.
4. Host antigen presenting cells can uptake different graft molecules and process and
present these antigens ( see figure 25.8 page 389 Roitt's Book).
Immunolgical components of rejection:
Fig: 1.1
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Dr. Fadwah Al-Ghalib
3rd year
Diagnostic Immunology
The Tempo (Rate) of Rejection:
Type of
Time taken
Immunological
Rejection
Hyperacute
explanation
Cause
Min-hours
Triggers type II
hypersensitivity
Days
Accelerated
Days- weeks
Acute
Triggers
Type
IV
hypersensitivity
Months-years
Chronic
Prevention of Rejection
Anti-donor Ab &
complement
1- blood transfusion
2- multiple pregnancy
3- Previous transplantation rejected
Prevented by careful Abs & HLA cross matching
Reactivation of T occur when the recipient has been exposed
cells
previously to low levels of donor tissue
antigens and makes a rapid memory response
when the donor organ is transplanted.
Primary
Occur when immunosuppressive therapy is
activation of T discontinued
cells
Unclear
The walls of the blood vessels in the graft
thicken and eventually become blocked
Can be reduced by:
1) tissue matching: (monozygote twins are perfectly matched)
- HLA Ags can be practically matched by serological tissue typing
- Graft survival when donor & recipient share the same MHC class II Ags (e.g
HLADR)
2) Immunosuppressive treatment:
 Ag non-specific:
1- X-ray: Abolishes activity of Immune system Graft recipient vulnerable to
infections
2- Steroids:
Suppress activated macrophages, Interfere with APC function,
Reduce MHC Ag expression
3- Cyclosporin:
a. Suppress Lymphokine production by Th cells
b. Reduce expression of IL-2 receptors on lymphocytes undergo
activation
4- Azathioprine: are Cytotoxic Drug
a. Prevent proliferation of activated Cells (e.g.Tc cells) by inhibiting DNA
replication.
b. Damages all the tissues of the body (bone marrow, intestinal epithilium, hair
follicle)
 Ag-Specific immune suppression: can be obtained by inducing tolerance to
MHC Ags in te individual receiving the transplant. Such as antiidiotype Abs
bind to specific HLA T- cell membrane receptors, leads the T cell unable to
interact with the MHC Ags on the graft cells.
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Dr. Fadwah Al-Ghalib
Diagnostic Immunology
3rd year
Laboratory Testing For Histocompatibility:
The purpose of the tissue typing laboratory is to assess donor-recipient compatibility
for HLA and ABO to analyze patient serum for lymphocytotoxic antibodies which
may be specific for the potential transplant donor.
•
Tissue typing by using flow cytometry to identify human leukocytes antigens
(HLA)
•
Serological Tissue Typing
•
Tissue Typing-mixed lymphocytes
Serological Tissue Typing (fig:1.2)
Principle:
•
Performed by adding typing antisera of defined specificity (e.g anti-HLA-BB)
•
Complement and trypan blue stain are added to the test
•
The trypan stain will stain dead cells with blue color
•
This indicates that the tested cells carry the antigen
Tissue-typing-mixed lymphocytes reaction (MLR) (fig: 1.3)
Principle:
•
The cells being tested are incubated with “typing cells” of known specificity
•
The tested cells will recognize the typing cells as foreign cells and proliferate
•
If the cells are carrying the same specificity as the typing cells they will not
proliferate.
Figure 1.2
Figure 1.3
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