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

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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

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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