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Transplantation Transplantation ImmunologyImmunology
Dr.CSBR.Prasad, M.D.
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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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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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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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Which is the most common Allograft procedure in
medicine?
Blood TransfusionBlood Transfusion
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Histocompatibility Antigens (HLA)
Chromosome # 6Identity of SELF
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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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MHC region on Chr# 6
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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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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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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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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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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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HLA systemHLA system
However, this huge number (1:30millions)
is reduced to thousands by
naturally occuring gene linkages called
“Linkage disequilibirum”APR-2015-CSBRP
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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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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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Choice of Donor - LivingChoice of Donor - Living
• Identical twin – best• Compatible HLA-A & B – next best
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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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Other factors influencing allograft survivalOther factors influencing allograft survival
• History of multiple transfusions - decreases• Previous pregancies – decreases• Pre-graft blood transfusion – improves
survival• Immunosuppressive Rx - improves
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Immunological rejection of allograftsImmunological rejection of allografts
There are THREE types of allograft rejection
1. Hyperacute rejection2. Acute rejection3. Chronic rejection
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Immunological rejection of allograftsImmunological rejection of allograftsThere 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 & ThrombosisOrgan becomes cyanotic, mottled, and flaccid Tissue infarction
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Immunological rejection of allograftsImmunological rejection of allograftsThere are THREE types of allograft rejection
1. Hyperacute rejection
2. Acute rejectionOccurs within 30-90 days of transplantDTH / IgG mediated NK-cell cytotoxicityVasculature is normal (except endothelitis)Intense mononuclear infiltrate in the organRapid fall in organ function
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Immunological rejection of allograftsImmunological rejection of allografts2 - Acute rejection
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Immunological rejection of allograftsImmunological rejection of allografts
There are THREE types of allograft rejection
1. Hyperacute rejection2. Acute rejection3. Chronic rejectionAfter months or yearsHumoral / CMI mediated damageProgressive loss of functionSclerosis APR-2015-CSBRP
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Chronic rejection
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Methods of Increasing Graft Methods of Increasing Graft Survival Survival
• HLA matching• ABO & P matching• Immunosuppressive Rx• Induction of donor-specific tolerance in
host T cells
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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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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 Organs Transplantation of Other Solid Organs
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GVHD
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GVHDGVHD
• Graft mounts an attack on the host tissue• Immunodeficiency is a common denominator• May occur in two situations
1-BM transplantation2-Inbred population
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GVHDGVHD
Manifestaions:• Skin rash with desquamation• Mucositis• Hepatitis
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Oral lichenoid mucosal reaction and periodontal disease, occurring as part of graft-versus-host disease
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Rash involving Palms & Soles• Meningococcemia• Reiter’s syndrome• Kawasaki, Measles, or
Toxic Shock Syndrome• Hand, Foot, and Mouth
Disease• Mercury poisoning in
children• Bacterial endocarditis• Tylosis
• Rocky Mountain Spotted Fever
• GVHD rash• Steven Johnson
syndrome• Secondary and
Congenital Syphilis• Acral lentiginous
melanoma• Typhus
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Hand Foot Mouth Disease
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Rocky Mountain spotted fever
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Secondary Syphilis
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E N D
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