IMMUNE REGULATION OF MURINE GRAFT-VERSUS-HOST DISEASE

点击翻译按钮获取中文摘要

Graft-versus-host disease (GVHD) is a common occurrence following bone marrow transplantation. Despite the use of major histocompatibility complex (MHC)-matched bone marrow donors and immunosuppression regimens following transplant, large numbers of patients still develop GVHD. These findings indicate that non-MHC loci play an important role in the regulation and induction of GVHD. The goal of these studies is to characterize non-MHC loci which are important for the regulation and induction of murine GVHD. These studies will use a murine model of GVHD in which chronic GVHD is induced by intravenous injection of DBA/2 spleen cells into unirradiated (C57BL/6 x DBA/2)F1 mice while injection of spleen cells from the other parental strain, C57BL/6, results in acute GVHD. The presence of in vivo cytolytic T lymphocytes and suppressor cells in the acute form but the chronic form of GVHD are some of the distinguishing characteristics of the two forms of GVHD. These differences have been shown to be regulated by non-MHC loci. Preliminary experiments using BXD recombinant inbred strains have identified a putative locus or loci mapping approximately 10 map units distal to Hbb on chromosome 7 that regulates in vivo CTL production. Backcross experiments will attempt to quantitate the number of loci that regulate each GVHD trait and to more precisely map the locus or loci on chromosome 7. Additional experiments will determine the strain distribution of the B6 and DBA/2 alleles regulating in vivo CTL production and will test if the locus or loci regulating CTL were transferred as passenger loci during the production of H-1 or Hbb congenic strains. Further experiments will attempt to define the characteristics of the recipient and donor cells which contribute to the inability of the DBA/2 spleen cells to generate in vivo CTL when injected into B6D2F1 recipients. CTL precursor frequency analysis will be done to verify the finding that DBA/2 CTL precursors are being eliminated and not suppressed. Because spleen cells from 30-40 week old DBA/2 mice respond differently in vivo than cells from 6-8 week old mice, these differences will be studied to determine the donor cells' role in the in vivo response.