HLA AND TRANSPLANTATION

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The long-term objective of this project is to identify the peptide epitopes of HLA against which antibodies and allograft immunity are directed. This knowledge will be used to devise more accurate means of matching organ transplant donors and recipients. Although the one-year organ transplant survival rates have improved dramatically in recent years/ the long-term half life of 7 years has remained unchanged. The late loss of grafts has been shown to be the result of histoincompatibility. Now that the amino acid sequences of HLA specificities are known# it should be possible to ascertain which positions on the molecule are immunogenic. This information will permit the development of more effective measures of matching for organ transplants. The immunogenic epitopes will be studied by two empirical methods: first, more than 50,000 sera samples will be analyzed to identify those that are directed against specific epitopes to see which epitopes are the targets of alloantibodies; the second method will be to see which incompatibilities result in allograft rejections. Incompatibilities for each of the variable amino acids can be examined for their impact on graft survival in actual transplant cases by using data accumulated by the UCLA and UNOS Transplant Registries. Recent studies on the effect of mismatching conformational epitopes will be extended. We will examine the possibility that certain incompatible peptides cannot be presented by the host MHC due to lack of fit within the groove. Molecular modelling computer software will be used to examine the effect of specific incompatibilities on the MHC molecule. Incompatibility for epitopes of the HLA C, DQ and DP loci will be examined.