MHC and transplantation MHC & Transplantation 周炫辰 邹知耕 张顺 郑艳 宗瑶 赵静

What is transplantation Transplantation In clinical practice,organ that has functional deficiency can be replaced by a normal organ from another person to make good a functional deficit,this therapy is called transplantation.

The first kidney transplant experiments were performed in humans in France using animal kidneys. o A surgeon inserted slices of rabbit kidney into a child suffering from kidney failure. Although “the immediate results were excellent” the child died about 2 weeks later.

Joeseph E. Murray and his colleagues at Peter Bent Brigham Hospital in Boston performed the first truly successful kidney transplant between a pair of identical twins. This was done without any immunosuppressive medication. More kidney transplants between identical twins were successfully performed, and some of those kidney recipients are still alive today

Graft Donor Recipient

Classification of transplantation autograft: the same individual isograft: genetically identical individuals, i.e., identical twins allograft: the same species xenograft: different species (according to source of graft)

The greatest problem the transplantation is faced with is the rejection that ensues After research,scientists have discovered that MHC play an important role in the rejection. If the MHC is not identical between donor and recipient,it will cause immune rejection, leading to the death of the graft.

MHC——Major histocompatibility complex A large cluster of linked genes that encodes two sets of highly polymorphic cell-surface proteins,termed as: class I MHC molecules → CD8 + T cells class II MHC molecules → CD4 + T cells

MHC is also called HLA complex in human, but H-2 complex in the mouse.

Functions of MHC molecules Present antigen to T cells and initiate immune respose. T cell is activated only when MHC molecules bind to antigenic peptides.

The structure of different MHC molecules are almost identical. The part of MHC molecule that is important in T cell recognition is the outer surface of the  helices which is highly conserved. The significant differences between two MHC molecules lie deep in the peptide-binding groove between the  helices,governing which peptide can bind.

Molecular basis for interaction of MHC molecules and antigenic peptide

Mechanism of rejection Graft and host MHC molecules present different peptides so that an immune response is triggerred.

Normal situation: MHCPeptide T cell activationTransplantation: MHC MHC Peptide 1.Direct recognition of alloantigens Rejection

1.Direct recognition of alloantigens The passenger leukocytes in the graft,that is the DCs and macrophages,also play an important role. Quickly Strongly

2. Indirect recognition of alloantigens Allotype MHC molecules can be as foreign protein processed by APC and recognized by T cell of recipient. The recipient T cells recognize the peptide that is processed by recipient APC and is from donor MHC molecules. Slowly Weakly

Role of CD4+ T cells and CD8+ T cells CTL MM MHC II of self-APC MHC II of graft-APC CD4+ T cell MHC I of self-APC CD8+ T cell (IL-2,IFN  ) NK B cell MHC I of graft-cell

Graft-versus-host reaction GVHR A special situation occurs in bone-marrow transplantation,in which GVHR is induced by immunologically competent T cells being transplantation into allogeneic recipients which are able to reject them.

Ways to prevent rejection Tissue typing (not completely) Immunosuppression (non-specific) Immunological tolerance (not practical)

Tissue typing by the mixed lymphocyte reaction (MLR)

Immunosuppressive agents application(s)mode of actionagent corticosteroids, prednisone anti-inflammatory, altering T-cell and PMN traffic organ transplant, hypersensitivity, autoimmunity cyclosporine, ticrolimus inhibition of IL-2 production by T cells organ transplant, rapamycin Inhibition of T cell activation by IL-2 organ transplant

Immunosuppressive agents application(s)mode of actionagent azathioprine, 6-MP purine metabolismorgan transplant methotrexatefolate metabolism organ transplant cyclophosphamide, melphalan alkylation of DNA, RNA and proteins autoimmune diseases, organ transplant x-irradiationLymphopenia malignancy/marrow transplantation

Alternative ways Stem cell Xenograft

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