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Major Histocompatibility Complex(MHC)

Major Histocompatibility Complex(MHC)

What is MHC?– HLA– H-2– Minor histocompatibility antigens

What is MHC?– HLA– H-2– Minor histocompatibility antigens

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Significance of the MHCSignificance of the MHC

role in immune response role in organ transplantation role in predisposition to disease

role in immune response role in organ transplantation role in predisposition to disease

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Genetic barriers to transplantationGenetic barriers to transplantation

• autologous: in the same individual

• isologous: between genetically Identical individuals, i.e., identical twins (inbred animals)

• homologous: between individuals of the same species

• heterologous: between individuals different species

• autologous: in the same individual

• isologous: between genetically Identical individuals, i.e., identical twins (inbred animals)

• homologous: between individuals of the same species

• heterologous: between individuals different species

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The laws of transplantationThe laws of transplantation

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Histocompatibility antigensand graft survival

Histocompatibility antigensand graft survival

minor histocompatibility antigens also cause rejection

The rejection time is variable but shorter than that for major histocompatibility antigen

They have additive effects

minor histocompatibility antigens also cause rejection

The rejection time is variable but shorter than that for major histocompatibility antigen

They have additive effects

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Graft versus host diseaseGraft versus host disease

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Graft versus host diseaseGraft versus host disease

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The human MHC genesThe human MHC genes

class II c lass ID P D Q D R B C A

B C A

D P D Q D R

1 2 2 2 1 1 9 3 1 2 2 1 3

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The mouse MHC genesThe mouse MHC genes

I

DK

A E

class II c lass Iclass I class III(C4, factor-B ,TNF, etc.)

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Polymorphism of MHC genesPolymorphism of MHC genes

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76

18 32

221188

4285

0

50

100

150

200

250

DPA DPB DQA DQB DRB B C A

10

76

18 32

221188

4285

0

50

100

150

200

250

DPA DPB DQA DQB DRB B C A

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The inheritance of MHC genesThe inheritance of MHC genes

Jack Jill

D P

D Q

D R

B

C

A

1 2 3 4

Bo Kim M o Lee

1 3 41 2 3 42

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MHC products expressed on cellsMHC products expressed on cells

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Crossing overresults in new haplotypes

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Class-I expressed on all nucleated cells in man, and also on erythrocytes in mice.

Class-II expressed primarily on antigen presenting cells (dendritic cells, macrophages and B cells)

Differential expression of MHC antigens

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Cytotoxic T lymphocyte (CTL) generation

Cytotoxic T lymphocyte (CTL) generation

CD4+TH1

CD8+CTL

CD8+preCTL

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Alloreactivity of T cellsAlloreactivity of T cells

T CELLT CELL

DRW 11DRW 17

PositiveSelection

ThymusAlloreaction

(MLR)

Proliferation and

Differentiation

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Inflammation

lysis

ADCC

lysis

IL2, IFN

TNF, NO2

IL2, IL4, IL5

IL2, TNF, IFN

rejection

Mechanisms of graft rejectionMechanisms of graft rejection

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Tempo of rejection reactionTempo of rejection reaction

chronic

type of rejection

accelerated

hyperacute

acute

months-years

time taken

minutes- hours

days

days-weeks

unclear causes: cross reactive Ab, immune complexes, slow cellular reaction, tolerance breakdown, disease recurrence

cause

preformed anti-donor antibodies and complement

reactivation of sensitized T cells (secondary response)

primary activation of T cells

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HLA matching and graft survivalHLA matching and graft survival

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Blood transfusion and graft survivalBlood transfusion and graft survival

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Immunosuppresseive agentsImmunosuppresseive agents

application(s)mode of actionagent

corticosteroids, prednisone

anti-inflammatory, altering T-cell and PMN traffic

organ transplant, hypersensitivity, autoimmunity

rapamycin Inhibition of T cell activation by IL-2

organ transplant

Cyclosporin, FK-506

inhibition of IL-2 production by T cells

organ transplant

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Immunosuppresseive agentsImmunosuppresseive agents

application(s)mode of actionagent

azathioprine, 6-MP purine metabolism

organ transplant

methotrexate folate metabolism organ transplant

cyclophosphamide, melphalan

alkylation of DNA, RNA and proteins

autoimmune diseases, organ transplant

x-irradiation Lymphopenia malignancy/marrow transplantation

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Removal of T cells from marrow graftRemoval of T cells from marrow graft

Magnet

Magnetic antibodies

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HLA and disease associationHLA and disease association

Disease Associated alleles Frequency in

Relative riskpatients control

Ankylsoing spondylitis

Reiter’s disease

Acute anterior uveitis

Psoriasis vulgaris

Dermatitis herpetiformis

B27

B27

B27

CW6

DR3

9

79

52

87

85

9

9

9

33

26

87.4

37.0

10.4

13.3

15.4