The long range goals of this application are to investigate the role of non HLA-A, B, C genes in the outcome of an unrelated donor marrow transplant. Although genetic matching of the classical class I antigens is clearly a major determinant of successful marrow transplant outcome, comparisons of the frequency of graft versus host disease (GVHD) in donor related transplants with that observed in unrelated transplants has shown that other polymorphic genetic factors must be involved. We would like to test the hypothesis that there exist non HLA-A, B, C genetic components within the major histocompatibility complex (MHC) which are not in linkage disequilibrium with the classical class I antigens and which consequently are mismatched in a large percentage of unrelated marrow transplants. We will further examine whether this genetic difference contributes to the observed difference in GVHD. In order to test this hypothesis, we have cloned the entire class I region spanning nearly 2.4 million base pairs including all of the class I genes. Having the entire class I region cloned has made it feasible to identify several new class I linked genes. Therefore it will be possible to examine the functional characteristics of the most polymorphic loci and subsequently their potential involvement in transplant outcome. Our previous work has provided two examples of non-HLA-A, B, C genes which fit the criteria of exhibiting polymorphism which is not in linkage disequilibrium with HLA classical class I, those being HLA-E and MICA. Thus, in an HLA-A, -B matched unrelated transplant, the likelihood of an HLA-E mismatched is high and of MICA being mismatched even higher.
The specific aims are to elucidate the large scale genomic diversity of the HLA class I region and to identify and characterize the structure and expression of specific polymorphic genes resident within the class I region. We will use this information to investigate the involvement of polymorphic genes other than HLA-A, B, C in a marrow transplant. This will be done by defining and measuring the extent of polymorphism and correlating polymorphism with transplant outcome in unrelated HLA identical transplants. We will also examine the potential for polymorphic portions of MHC resident proteins to be presented by classical class I. The recognition of a new polymorphic locus in the MHC presents new possibilities for investigating the basis for GVHD in HLA-matched unrelated donor-recipient pairs. Genetic factors related to the MHC have been postulated to influence the immune response to allogeneic marrow, but their definition has remained elusive. We are now poised to identify such loci and thoroughly explore their potential involvement in the outcome of an unrelated marrow transplant.
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