Major Histocompatibility Complex MHC What is MHC HLA

Major Histocompatibility Complex (MHC) Ø What is MHC? – – – HLA H-2 Minor histocompatibility antigens 2

Significance of the MHC role in immune response Ø role in organ transplantation Ø role in predisposition to disease Ø 3

Genetic 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) 5

Principles of transplantation 6

Minor histocompatibility antigens and graft survival Ø minor histocompatibility antigens also cause rejection Ø The rejection time is variable but longer than that for major histocompatibility antigen Ø They have additive effects 7

Graft versus host (GVH) disease 8

GVH disease in humans 9

The human MHC genes 10

The mouse MHC genes 11

The inheritance of MHC genes 13

Crossing over results in new haplotypes 14

MHC 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 15

Differential expression of MHC antigens Ø Class-I expressed on all nucleated cells in man, and also on erythrocytes in mice. Ø Class-II expressed primarily on antigen presenting cells (dendritic cells, macrophages and B cells, etc. ) 16

Alloreactivity of T cells: MLR and CTL generation CD 4+TH 1 CD 8+pre. CTL CD 8+CTL 17

Alloreactivity of T cells Alloreaction (MLR) Thymus Positive Selection Proliferation and Differentiation 18

Mechanisms of graft rejection IL 2, TNF , IFN TNF , NO 2 Inflammation IL 2, IL 4, IL 5 IL 2, IFN lysis ADCC lysis rejection 19

Tempo of rejection reaction type of rejection hyperacute accelerated time taken minutes- hours days acute days-weeks chronic months-years cause preformed anti-donor antibodies and complement reactivation of sensitized T cells (secondary response) primary activation of T cells unclear causes: cross reactive Ab, immune complexes, slow cellular reaction, tolerance breakdown, disease recurrence 20

A, B & DR matching and graft survival 21

Removal of T cells from marrow graft Magnetic antibodies Magnet 22

HLA and disease association Disease Associated alleles Frequency in patients Ankylsoing spondylitis Reiter’s disease Acute anterior uveitis Psoriasis vulgaris Dermatitis herpetiformis B 27 CW 6 DR 3 9 79 52 87 85 control 9 9 9 33 26 Relative risk 87. 4 37. 0 10. 4 13. 3 15. 4 23

a b c d ac ATCGGTCAAGGCCTATCGATTGCGTAGGC bd ATCGGTCAAGGCCTATCGATTGCGTAGGC ac ATCGGTCAAGGCCTATCGATTGCGTAGGC ad ATCGGTCAAGGCCTATCGATTGCGTAGGC bc ATCGGTCAAGGCCTATCGATTGCGTAGGC 34

根据片段组合指定等位基因 ac ef ac ox ac gh rt ef wq ad ml sv bd jk zp bc 35