Transplantation immunology overview
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Transplantation immunology overview

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    Transplantation immunology overview Transplantation immunology overview Presentation Transcript

    •   Terminology Basis of rejection    Effector mechanisms in rejection    Role of HLA system and T cells ABO antigens Immunological recognition of alloantigens Types of rejection Anti-rejection strategies
    •  Karl Landsteiner (1868-1943)   Peter Medawar (1915-1987)   ABO blood group system Skin grafts and specific memory George Snell (1903-1996)  MHC genetics, basis of rejection
    •  Transplantation:   Graft:     transfer of cells, tissues or organs between two individuals (or between different sites in an individual)…… also see transfusion The transplanted organ…. cornea, heart, kidney, liver, lung, pancreas, blood Donor: individual who provides the graft Recipient: individual receiving the graft Rejection: failure of transplanted graft to survive in recipient
    •  Autologous graft (autograft)   Syngeneic graft (isograft)   Transplant between two genetically identical individuals Allogeneic graft (allograft)   Transplant within an individual Transplant between two genetically different individuals of the same species (most common) Xenogeneic graft (xenograft)  Transplant between two individuals from different species (experimental)
    •      The major histocompatibility complex (MHC) is found in all vertebrates. Displays extensive genetic polymorphism. Polymorphic differences affect peptide-binding region on MHC molecules. Ensures presentation of a wide range of antigenic peptides. Differences between individuals responsible for graft rejection (origin of term ‘histocompatibility’).
    •       T cells subsets include: CD4+ - T-helper (TH) cells. CD8+ - T-cytotoxic (Tc) cells. CD4+ recognise antigenic peptide bound to MHC class II molecules. CD8+ recognise antigenic peptide bound to MHC class I molecules. MHC presentation is an absolute requirement.
    • Peptide binding site Peptide binding site chain chain 2 microglobulin chain
    • TAPs MHC class I presentation Viral protein Proteasome processing peptides MHC class I RER Plasma membrane
    • Trapped Ag proteolysis peptides fusion Invariant chain (Ii) Ii removed in endosome Transport through Golgi RER MHC class II molecule MHC class II presentation
    •       Highly polymorphic gene cluster on chromosome 6 Multiple allelic forms exist at different loci HLA class I encoded at 3 loci – A,B,C HLA class II encoded at 3 loci in D region HLADR, DP and DQ Parental haplotypes inherited in Mendelian fashion Parental MHC alleles are codominantly expressed
    • HLA CLASS II DP DQ HLA CLASS I DR multiple DR B C A
    •      Class I consist of a heterodimer HLA-encoded chain Second chain – 2-microglobulin is not MHCencoded Alpha chain contains peptide-binding site Present peptides to CD8+ T cells
    •       Composed of an heterodimer Both chains are encoded in HLA 2 or more genes for Present antigenic peptide to CD4+ T cells Peptide binding site formed by parts of both chains More extensive polymorphism than class I
    •      Class I consist of a heterodimer HLA-encoded alpha chain 2 microglobulin Alpha chain contains peptide-binding site Present peptides to CD8+ T cells
    •       Composed of an heterodimer Both chains are encoded in HLA 2 or more genes for Present antigenic peptide to CD4+ T cells Peptide binding site formed by parts of both chains HLA DR 4 associated with RA   chain of HLA DR4 Risk factor ~ 6
    •   Encoded at the HLA-A, -B and –C loci. Allelic variations:     >350 alleles at A locus >650 alleles at B locus ~190 alleles at C locus Possible combinations ~45 million different class I haplotypes.
    •  Encoded at three loci in the D region.       DP – two gene and genes DQ – two genes and 3 genes DR – one gene, multiple genes Possible combinations within the population ~ 1012 Total HLA combinations ~ 1020. Note: many polymorphisms are not clinically relevant!
    •       MHC named due to role in graft rejection. Highly polymorphic region on human chromosome 6. Polymorphism affects peptide-binding region. Essential for T cell responses. Different responses to pathogens within population Certain allelic forms associated with presentation of self-peptide – autoimmunity!