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1
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
3
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
4
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
7
Graft versus host diseaseGraft versus host disease
8
Graft versus host diseaseGraft versus host disease
9
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
10
The mouse MHC genesThe mouse MHC genes
I
DK
A E
class II c lass Iclass I class III(C4, factor-B ,TNF, etc.)
11
Polymorphism of MHC genesPolymorphism of MHC genes
10
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
12
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
13
MHC products expressed on cellsMHC products expressed on cells
14
Crossing overresults in new haplotypes
15
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
20
HLA matching and graft survivalHLA matching and graft survival
21
Blood transfusion and graft survivalBlood transfusion and graft survival
22
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
23
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
24
Removal of T cells from marrow graftRemoval of T cells from marrow graft
Magnet
Magnetic antibodies
25
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