1 Major Histocompatibility Complex (MHC) What is MHC? – HLA – H-2 (in the mouse) – Minor...
-
Upload
jennifer-barr -
Category
Documents
-
view
229 -
download
1
Transcript of 1 Major Histocompatibility Complex (MHC) What is MHC? – HLA – H-2 (in the mouse) – Minor...
1
Major Histocompatibility Complex(MHC)
Major Histocompatibility Complex(MHC)
What is MHC?– HLA– H-2 (in the mouse)– Minor histocompatibility antigens
What is MHC?– HLA– H-2 (in the mouse)– Minor histocompatibility antigens
2
There may be polymorphic antigens other than MHC that differ between the donor and the recipient.
These antigens induce weak or slower ( more gradual) rejection reactions than do MHC molecules and are called Minor histocompatibility antigens.
There may be polymorphic antigens other than MHC that differ between the donor and the recipient.
These antigens induce weak or slower ( more gradual) rejection reactions than do MHC molecules and are called Minor histocompatibility antigens.
3
Minor histocompatibility antigens are proteins that are processed an presented to host T cells association with self MHC molecules on host APCs (by indirect pathway).
Minor histocompatibility antigens are proteins that are processed an presented to host T cells association with self MHC molecules on host APCs (by indirect pathway).
4
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
7
Genetic barriers to transplantationGenetic barriers to transplantation
• autologous: in the same individual (autograft)
• isologous: between genetically Identical individuals (isograft), i.e., identical twins (inbred animals)
• homologous: between individuals of the same species (allograft)
• heterologous: between individuals different species (xenograft)
• autologous: in the same individual (autograft)
• isologous: between genetically Identical individuals (isograft), i.e., identical twins (inbred animals)
• homologous: between individuals of the same species (allograft)
• heterologous: between individuals different species (xenograft)
8
Principles of transplantationPrinciples of transplantation
9
Minor histocompatibility antigensand graft survival
Minor histocompatibility antigensand graft survival
minor histocompatibility antigens also cause rejection
The rejection time is variable but longer than that for major histocompatibility antigen
They have additive effects
minor histocompatibility antigens also cause rejection
The rejection time is variable but longer than that for major histocompatibility antigen
They have additive effects
10
Graft versus host (GVH) diseaseGraft versus host (GVH) disease
11
GVH disease in humansGVH disease in humans
12
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
13
The mouse MHC genesThe mouse MHC genes
I
DK
A E
class II c lass Iclass I class III(C4, factor-B ,TNF, etc.)
14
Polymorphism of MHC antigens (based on phenotype)
Polymorphism of MHC antigens (based on phenotype)
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
15
Polymorphism of MHC genes(based on DNA sequence/ PCR)
Polymorphism of MHC genes(based on DNA sequence/ PCR)
2096
22 481
360460
110220
0100200300400500
2096
22 481
360460
110220
0100200300400500
16
MHC products expressed on cellsMHC products expressed on cells
If Jack and Jill have four children; Bo, Kim, Mo and Lee
They’ll all inherit antigens of the parental MHC
Oft their haplotypes will be of the father or mother
Unless during meiosis, a crossover should occur
17
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
18
MHC products expressed on cellsMHC products expressed on cells
19
Crossing overresults in new haplotypes
20
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, etc.)
Differential expression of MHC antigens
21
Alloreactivity of T cells:MLR and CTL generationAlloreactivity of T cells:
MLR and CTL generation
CD4+TH1
CD8+CTL
CD8+preCTL
22
Alloreactivity of T cellsAlloreactivity of T cells
T CELLT CELL
DRW 11DRW 17
PositiveSelection
ThymusAlloreaction
(MLR)
Proliferation and
Differentiation
23
Inflammation
lysis
ADCC
lysis
IL2, IFN
TNF, NO2
IL2, IL4, IL5
IL2, TNF, IFN
rejection
Mechanisms of graft rejectionMechanisms of graft rejection
24
Tempo of rejection reactionTempo of rejection reaction
type of rejection
time taken cause
chronic months-years unclear causes: cross reactive Ab, immune complexes, slow cellular reaction, tolerance breakdown, disease recurrence
accelerated days reactivation of sensitized T cells (secondary response)
acute days-weeks
primary activation of T cells
hyperacute minutes- hours preformed anti-donor antibodies and complement
25
Immunosuppressive agentsImmunosuppressive 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
cyclosporine, ticrolimus
inhibition of IL-2 production by T cells
organ transplant,
26
Immunosuppressive agentsImmunosuppressive 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
27
Removal of T cells from marrow graftRemoval of T cells from marrow graft
Magnet
Magnetic antibodies
28
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