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. Unfortunately, less than 30% of patients in the United States have an HLA identical sibling, and thus many are denied the opportunity for a potentially curative treatment for otherwise fatal conditions. The recent development of a national registry of volunteer bone marrow donors (the National Marrow Donor Program) has made it possible to efficiently access the centralized file of more than 40,000 HLA typed volunteers. Unrelated donor marrow transplants have become a reality, however, our preliminary clinical experience has clearly demonstrated that biological complications of allografting and clinically significant graft-versus-host disease (GVHD) are increased in incidence and severity. We believe that the likely cause of these problems is a lack of precision in standard HLA typing and an inability to provide for sufficient donor and recipient matching. The objectives of this Program Project are to apply molecular technology to HLA typing and donor matching. HLA matching alone, however, will not solve all problems related to donor selection and successful marrow transplantation. Many patients will never find a genotypically identical donor. The alternative approach to successfully treating these patients will depend on improving our understanding of T cell responses to alloantigen and the development of more rational approaches to modifying the immune system of the chimeric marrow transplant recipient. There are six projects in this Program Project application. Project 1 is a study of the polymorphism and functional significance of the new class I HLA-E, F(5.4) and G(6.0) genes. Project 2 is a study of molecular variance among classical 1 HLA-A,B,C antigens defined by standard serology. Isoelectric-focusing gel electrophoresis (IEF) and cytotoxic T lymphocyte (CTL) clones are used to identify previously unrecognized variants. The cDNA encoding these variants are sequenced and new oligonucleotide probes developed for prospective typing. Project 3 is a study of molecular variants among the class II HLA-DR, DQ AND DP genes. New variants will be identified by T cell clones, sequenced and oligonucleotide probes developed for prospective typing. Project 4 is a study of in vitro methods for inducing specific nonresponsiveness to alloantigen with anti-CD3 antibody or alternatively, by depleting specific alloreactive subsets in vitro. T cells rendered nonresponsive in vitro will be tested in an in vivo murine transplant model to determine if they are capable of modifying GVHD. Project 5 is a study of nonresponsiveness in vitro achieved by induction of alloantigen specific suppressor cells. Project 6 is a combined research project and core facility that provides administrative services, a cell bank for clinical materials, a centralized HLA and clinical transport data base. The research question addressed in Project 6 is whether the microvariants defined by individual HLA alleles have a significant impact on GVHD.
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