Allogeneic marrow transplants from HLA genotypically identical siblings have become life-saving therapy for patients with various congenital and acquired diseases of the immune and hematopoietic systems. Graft-versus- host disease (GVHD), however, remains a significant cause of morbidity and mortality. Nonspecific immunosuppression developed through empirical trials has provided increasingly better GVHD control, but these agents are potentially toxic, they delay immunoreconstitution and increase risk of infection. In some cases immunosuppression administered for GVHD prophylaxis can abrogate the graft-versus-leukemia (GVL) effect that can occur following marrow allografting. The success of marrow allografts has drawn attention to the problem of donor availability, and less than 30% of patients in the United States have an HLA identical sibling, and thus many are denied the opportunity foe a potentially curative treatment for otherwise fatal disease. The development of a national registry of potential marrow donors by the National Marrow Donor Program (NMDP) has made it possible to access a centralized of more than 500,000 HLA typed volunteers. Unrelated donor transplants are becoming a reality for increasing numbers of patients. Our preliminary clinical experience, however has demonstrated that GVHD is increased in both incidence and severity in unrelated donor transplants. This may be explained by a lack of precision in HLA typing and an inability to achieve sufficient donor and recipient HLA matching. However, incompatibility for non-HLA minor histocompatibility determinants may also play a role. The objectives of this Program Project involve two strategies. The first is to apply molecular technology to HLA typing and donor matching. Improved HLA typing, however may not solve all problems related to donor selection because many patients will never find a perfectly matched donor. Successful management of these patients will depend on improving our understanding of T cell responses to alloantigen and development of more rational effective approaches to achieving tolerance. There are five projects in the Program Project application. Project 1 includes new studies aimed at uncovering polymorphic loci residing within the HLA class I region and continues studies of the polymorphism and functional significance of the nonclassical antigens. Project 2 is a study of HLA- A, B, C molecular variants and their significance in unrelated marrow- donor matching. Project 3 seeks to develop and evaluate cytotoxic agents directed against IL-2 receptors as a possible method of preventing GVHD. Project 4 studies the requirements for induction of T cell tolerance to allogeneic hematopoietic stem cells. Project 5 is a combined research project and core facility that provides administrative services, maintains a cell and DNA bank and a centralized HLA-clinical transplant data base. The research questions addressed in Project 5 is whether the microvariants defined by individual HLA class I alleles have significant effect on risk of rejection and GVHD.
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