Allogeneic bone marrow transplantation (BMT) following myeloablation is the treatment of choice for many forms of neoplasm, including leukemia and lymphoma. However, even when donor and recipient are matched for Major Histocompatibility Complex (MHC) antigens, successful reconstitution often results in serious graft vs. host disease (GVHD) because so-called minor histocompatibility antigens (miHA) encoded outside of the MHC act as targets of the GVH response. However, studies in humans and in mice have suggested that a small number of dominant miHA may play a disproportionately major role in serious GVHD. Thus, a key unsolved issue is how many miHA are functionally significant during allogeneic BMT under conditions of MHC matching? The applicant's overall goal is to define the miHAs that dominate GVHD in mice, and to then determine whether he can use this information toward risk assessment and/or therapeutic regimes. Cytotoxic T lymphocytes (CTLs) are thought to play a pivotal role in serious GVHD and he has already identified one mouse miHA, H60, which is the major target of CTLs during serious GVHD. He will determine whether additional miHAs that also dominate during GVH, which will constitute the first thorough analysis in humans or mice of GVHD-associated miHAs. There is remarkably little information regarding the dynamics of CTLs in the GVH response. The applicant will use available miHA/MHC tetramers to track specific CTLs during GVHD. This should provide new insights into the dynamics and fate of CTLs engaging in systemic immune responses in vivo. If he finds that the number of functionally important miHA is low, these dominant miHAs should have a disproportionately large effect in causing GVHD. He will test this possibility by determining: (1) whether severe GVHD can be reconstructed by mismatching only at these miHAs; and (2) whether donors and recipients matched for (or tolerized to) a limited number of GVH-associated miHAs but mismatched for all others are protected from serious GVHD. In summary, GVHD is a complex genetic disease caused by a potentially large number of miHAs. However, studies have suggested that certain miHAs play a disproportionately major role in serious GVHD. The applicant's proposed studies should resolve this enigma, and in doing so, the studies should clarify the immunogenetics of GVHD and provide a feasibility study of how genomic data might be exploited to improve allogeneic BMT.
| Brown, Aaron C; Kai, Kristin; May, Marjorie E et al. (2004) ExQuest, a novel method for displaying quantitative gene expression from ESTs. Genomics 83:528-39 |
| Yadav, Rajwardhan; Yoshimura, Yoshitaka; Boesteanu, Alina et al. (2003) The H4b minor histocompatibility antigen is caused by a combination of genetically determined and posttranslational modifications. J Immunol 170:5133-42 |
| Sproule, T J; Jazwinska, E C; Britton, R S et al. (2001) Naturally variant autosomal and sex-linked loci determine the severity of iron overload in beta 2-microglobulin-deficient mice. Proc Natl Acad Sci U S A 98:5170-4 |
| Fleming, R E; Holden, C C; Tomatsu, S et al. (2001) Mouse strain differences determine severity of iron accumulation in Hfe knockout model of hereditary hemochromatosis. Proc Natl Acad Sci U S A 98:2707-11 |
