2. Organ transplantation is the Rx of choice
when an organ …..
- has severe congenital malformation
- is irreversibly damaged by some disease
process
Main obstacle is rejection of
transplanted organ by the host
Transplantation Immunology
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3. Transplantation - terminologyTransplantation - terminology
• Autograft – Donor & recipient is same
individual
• Isograft - Donor & recipient is same
genotype
• Allograft - Donor & recipient is of same
species but different genotype
• Xenograft – Donor is different species from
that of recipient
Skin , kidney, BM, heart, lung, liver, cornea
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4. Transplant rejectionTransplant rejection
• Any two individuals express 2 different
HLA protein
• Rejection is a complex process in which
both cell mediated immunity & circulating
Ab play a role
• T cell mediated reaction
– CD4 + helper cells – mediate Delayed
hypersensitivity reaction
– CD8+ CTLS – mediate graft cell destruction
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5. Which is the most common
Allograft procedure in
medicine?
Blood TransfusionBlood Transfusion
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7. Histo-compatibility AntigenHisto-compatibility Antigen
• Base on structure, distribution and
function of MHC gene products
• Class I MHC antigens have loci as HLA-
A, HLA – B and HLA – C
• Class II MHC antigens have single locus
HLA – D . It has 3 subregions – HLA- DP,
HLA-DQ and HLA- DR
• Class III genes - Complement
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9. Class I MHC antigensClass I MHC antigens
• Expressed on all nucleated cells & platelet
• It binds to peptides that are derived from
proteins such as viral antigens
• Cells process the antigen and transported
to cell surface for presentation to CD8
cytotoxic T lymphocytes
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10. Figure 6-10 Antigen
processing and recognition.
The sequence of events in
the processing of a
cytoplasmic protein antigen
and its display by class I
MHC molecules are shown
at the top. The recognition
of this MHC-displayed
peptide by a CD8+ T cell is
shown at the bottom.
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11. Class II MHC antigensClass II MHC antigens
• Present only on APC – Macrophages,
Dendritic cells & B cells
• It binds to exogenous antigens (microbes,
soluble proteins) that are first internalised
and processed in endosomes / lysosomes
• Peptide - MHC complex is transported to
the cell surface, where it is recognized by
CD4 helper T cells
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12. The T-cell receptor (TCR) complex:
B, Recognition of MHC-
associated peptide displayed on
an antigen-presenting cell (top)
by the TCR. Note that the TCR-
associated ζ chains and CD3
complex deliver signals (signal
1) upon antigen recognition, and
CD28 delivers signals (signal 2)
upon recognition of
costimulators (B7 molecules).
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13. HLA systemHLA system
• Five HLA genes
• Ten possible loci
• Large # of different determinants
(A-17, B-27, C-6, D-11 & DRw-8)
• Codominants
• 30million unique combinations
(where there is no significant interbreeding)
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14. HLA systemHLA system
However, this huge number
(1:30millions)
is reduced to thousands by
naturally occuring gene linkages
called
“Linkage disequilibirum”
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15. Linkage disequilibriumLinkage disequilibrium
• Population studies have shown certain
combinations of
– A&B
– A&C
– B&D
occur together more commonly than expected
from random inheritance
Eg: Caucasians have HLA-A1, B8 and DRw3 profile
• Cross-over between the HLA-A and D loci rarely
occurs (<1% of births)
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16. Choice of DonorChoice of Donor
• Close HLA match is required to….
Reduce the chances of rejection and
Reduce the dosage of immunosuppressives
• ABO & P blood group compatible
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17. Choice of Donor - LivingChoice of Donor - Living
• Identical twin – best
• Compatible HLA-A & B – next best
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18. Choice of Donor - CadaverChoice of Donor - Cadaver
• Compatibility to 3 to 4 antigens of A&B
improves survival of the graft
• HLA-B match is very important
• HLA-C match has very limited role
• HLA-DR compatibility is required but, it’s
difficult to comply with
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20. Immunological rejection of allograftsImmunological rejection of allografts
There are THREE types of allograft rejection
1. Hyperacute rejection
2. Acute rejection
3. Chronic rejection
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21. Immunological rejection of allograftsImmunological rejection of allografts
There are THREE types of allograft rejection
1. Hyperacute rejection:
Occurs immediately after establishing circulation
(minutes to hours)
Due to preformed cytotoxic Abs
Result: Vascular injury & Thrombosis
Organ becomes cyanotic, mottled, and flaccid
Tissue infarction
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23. Immunological rejection of allograftsImmunological rejection of allografts
There are THREE types of allograft rejection
1. Hyperacute rejection
2. Acute rejection
Occurs within 30-90 days of transplant
DTH / IgG mediated NK-cell cytotoxicity
Vasculature is normal (except endothelitis)
Intense mononuclear infiltrate in the organ
Rapid fall in organ function
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24. Immunological rejection of allograftsImmunological rejection of allografts
2 - Acute rejection
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25. Immunological rejection of allograftsImmunological rejection of allografts
There are THREE types of allograft rejection
1. Hyperacute rejection
2. Acute rejection
3. Chronic rejection
After months or years
Humoral / CMI mediated damage
Progressive loss of function
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27. Methods of Increasing GraftMethods of Increasing Graft
SurvivalSurvival
• HLA matching
• ABO & P matching
• Immunosuppressive Rx
• Induction of donor-specific tolerance in
host T cells
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28. The T-cell receptor (TCR) complex:
B, Recognition of MHC-
associated peptide displayed on
an antigen-presenting cell (top)
by the TCR. Note that the TCR-
associated ζ chains and CD3
complex deliver signals (signal
1) upon antigen recognition, and
CD28 delivers signals (signal 2)
upon recognition of
costimulators (B7 molecules).
APR-2015-CSBRP
29. HLA matching is not done in the case of:
Heart, Lung, Pancreas, Liver transplants
Rejection reaction against liver transplants
is not as vigorous as might be expected
from the degree of HLA disparity
Exact mechanisms not known
Transplantation of Other Solid OrgansTransplantation of Other Solid Organs
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31. GVHDGVHD
• Graft mounts an attack on the host tissue
• Immunodeficiency is a common denominator
• May occur in two situations
1-BM transplantation
2-Inbred population
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Figure 6-4 The T-cell receptor (TCR) complex. A, Schematic illustration of TCRα and TCRβ chains linked to the CD3 complex. B, Recognition of MHC-associated peptide displayed on an antigen-presenting cell (top) by the TCR. Note that the TCR-associated ζ (Zeta) chains and CD3 complex deliver signals (signal 1) upon antigen recognition, and CD28 delivers signals (signal 2) upon recognition of costimulators (B7 molecules).
έ = Epslon
i.e. A&D go together. Therefore siblings who are identical for HLA-A&B loci are usually identical for HLA-D as well, something found in only 10% of unrelated donors.
Complications with immunosuppressive therapy: Fatal infections, DM, Cataract and Malignancies.
In a given family of siblings there is 1in4 chances for identicality (A&B) and 1in2 chances of having one identical allele (haplotype).
In a given family of siblings there is 1in4 chances for identicality (A&B) and 1in2 chances of having one identical allele (haplotype).
Occurs immediately after establishing circulation (minutes to hours)
Due to preformed cytotoxic Abs against HLA or ABO Ags
Result: Vascular injury & Thrombosis
Organ becomes cyanotic, mottled, and flaccid
Tissue infarction
Kidney Transplantation Graft Rejection
Figure 6-24 Acute cellular rejection of a renal allograft. A, An intense mononuclear cell infiltrate occupies the space between the tubules. B, T cells (stained brown by the immunoperoxidase technique) are abundant in the interstitium and infiltrating a tubule. (Courtesy of Dr. Robert Colvin, Department of Pathology, Massachusetts General Hospital, Boston, MA.)
In addition to causing tubular damage, CD8+ cells may also injure vascular endothelial cells, causing a so-called endothelitis. This form of cell-mediated vascular damage is limited to the endothelium and is distinct from the antibody-mediated vasculitis described later. The affected vessels have swollen endothelial cells, and at places the lymphocytes can be seen between the endothelium and the vessel wall. The recognition of cellular rejection is important because, in the absence of an accompanying arteritis, patients promptly respond to immunosuppressive therapy. Cyclosporine, a widely used immunosuppressive drug, is also nephrotoxic, and hence the histologic changes resulting from cyclosporine may be superimposed.
Figure 6-26 Chronic rejection in a kidney allograft. A, Changes in the kidney in chronic rejection. B, Graft arteriosclerosis. The vascular lumen is replaced by an accumulation of smooth muscle cells and connective tissue in the vessel intima. (Courtesy of Dr. Helmut Rennke, Department of Pathology, Brigham and Women&apos;s Hospital and Harvard Medical School, Boston, MA.)
Chronic rejection is dominated by vascular changes, interstitial fibrosis, and tubular atrophy with loss of renal parenchyma ( Fig. 6-26 ). The vascular changes consist of dense, obliterative intimal fibrosis, principally in the cortical arteries. These vascular lesions result in renal ischemia, manifested by glomerular loss, interstitial fibrosis and tubular atrophy, and shrinkage of the renal parenchyma. The glomeruli may show duplication of basement membranes; this appearance is sometimes called chronic transplant glomerulopathy. Chronically rejecting kidneys usually have interstitial mononuclear cell infiltrates containing large numbers of plasma cells and numerous eosinophils.
Although immunosuppression has produced significant gains in terms of graft survival, immunosuppressive therapy carries its own risks. The price paid in the form of increased susceptibility to opportunistic fungal, viral, and other infections is not small. These patients are also at increased risk for developing EBV-induced lymphomas, human papillomavirus-induced squamous cell carcinomas, and Kaposi sarcoma ( Chapter 11 ). To circumvent the untoward effects of immunosuppression, much effort is being devoted to induce donor-specific tolerance in host T cells.[33] One strategy being pursued in experimental animals is to prevent host T cells from receiving costimulatory signals from dendritic cells during the initial phase of sensitization. This can be accomplished by interrupting the interaction between the B7 molecules on the dendritic cells of the graft donor with the CD28 receptors on host T cells, as, for example, by administration of proteins that bind to B7 costimulators. This, as discussed earlier, interrupts the second signal for T-cell activation and renders the T cells anergic or induces their apoptosis. Antibodies that block CD40 ligand are also being tried; they presumably work by inhibiting humoral immune responses and CTL generation. In addition, giving donor cells to graft recipients may prevent reactions to the graft, perhaps because the donor inoculum contains cells, such as immature dendritic cells, that induce tolerance to the donor alloantigens. This approach may result in long-term mixed chimerism, in which the recipient lives with the injected donor cells. Such approaches are being tried in patients.
Figure 6-4 The T-cell receptor (TCR) complex. A, Schematic illustration of TCRα and TCRβ chains linked to the CD3 complex. B, Recognition of MHC-associated peptide displayed on an antigen-presenting cell (top) by the TCR. Note that the TCR-associated ζ (Zeta) chains and CD3 complex deliver signals (signal 1) upon antigen recognition, and CD28 delivers signals (signal 2) upon recognition of costimulators (B7 molecules).
έ = Epslon
Although immunosuppression has produced significant gains in terms of graft survival, immunosuppressive therapy carries its own risks. The price paid in the form of increased susceptibility to opportunistic fungal, viral, and other infections is not small. These patients are also at increased risk for developing EBV-induced lymphomas, human papillomavirus-induced squamous cell carcinomas, and Kaposi sarcoma ( Chapter 11 ). To circumvent the untoward effects of immunosuppression, much effort is being devoted to induce donor-specific tolerance in host T cells.[33] One strategy being pursued in experimental animals is to prevent host T cells from receiving costimulatory signals from dendritic cells during the initial phase of sensitization. This can be accomplished by interrupting the interaction between the B7 molecules on the dendritic cells of the graft donor with the CD28 receptors on host T cells, as, for example, by administration of proteins that bind to B7 costimulators. This, as discussed earlier, interrupts the second signal for T-cell activation and renders the T cells anergic or induces their apoptosis. Antibodies that block CD40 ligand are also being tried; they presumably work by inhibiting humoral immune responses and CTL generation. In addition, giving donor cells to graft recipients may prevent reactions to the graft, perhaps because the donor inoculum contains cells, such as immature dendritic cells, that induce tolerance to the donor alloantigens. This approach may result in long-term mixed chimerism, in which the recipient lives with the injected donor cells. Such approaches are being tried in patients.
Acute GVH disease occurs within days to weeks after allogeneic bone marrow transplantation. Although any organ may be affected, the major clinical manifestations result from involvement of the immune system and epithelia of the skin, liver, and intestines. Involvement of skin in GVH disease is manifested by a generalized rash leading to desquamation in severe cases. Destruction of small bile ducts gives rise to jaundice, and mucosal ulceration of the gut results in bloody diarrhea. Despite considerable tissue damage, the affected tissues are not heavily infiltrated by lymphocytes. It is believed that in addition to direct cytotoxicity by CD8+ T cells, considerable damage is inflicted by cytokines released by the sensitized donor T cells.
Acute GVH disease occurs within days to weeks after allogeneic bone marrow transplantation. Although any organ may be affected, the major clinical manifestations result from involvement of the immune system and epithelia of the skin, liver, and intestines. Involvement of skin in GVH disease is manifested by a generalized rash leading to desquamation in severe cases. Destruction of small bile ducts gives rise to jaundice, and mucosal ulceration of the gut results in bloody diarrhea. Despite considerable tissue damage, the affected tissues are not heavily infiltrated by lymphocytes. It is believed that in addition to direct cytotoxicity by CD8+ T cells, considerable damage is inflicted by cytokines released by the sensitized donor T cells.
Early, chronic graft-versus-host reaction with widespread, almost confluent hyperpigmented lichenoid papules and toxic epidermal necrosis-like appearance on knee.
Late, chronic graft-versus -host reaction with hyperpigmented sclerotic plaques on the back.
Acute graft-versus-host reaction with vivid palmar erythema
Acute graft-versus-host reaction with vivid palmar erythema
Graft-versus-host reaction with early, chronic, diffuse, widespread lichenoid changes of lips
Oral lichenoid mucosal reaction and periodontal disease, occurring as part of graft-versus-host disease