Bone marrow transplantation is currently used to treat a wide range of diseases. At present, the mortality rate associated with this procedure is unacceptably high, primarily because of graft-versus-host disease (GVHD). Current clinical approaches to overcoming GVHD rely on the use of potent immunosuppressive drugs and T cell-depletion of bone marrow. Both of these treatments have adverse side effects. Immunosuppressive drugs inevitably render the patient more susceptible to infection while T cell-depletion is associated with increased risk of graft failure and of leukemic relapse. It is likely that better solutions to the problem of GVHD will only be developed after the fundamental immunological mechanisms of this syndrome are understood. The current project aims to investigate GVHD in a new way. Using a specific murine model in which the development of acute versus chronic GVHD appears to be influenced by non MHC """"""""background"""""""" genes, this project aims to use current genetic mapping techniques to identify genetic loci which affect the occurrence, severity or associated pathology of GVHD can be investigated. This approach has a major advantage over conventional investigations of GVHD in that no assumptions are made concerning the types of molecules/mechanisms involved - any locus affecting GVHD outcome through any mechanism will be identified. The project has three specific aims: 1) Identify genetic loci whose products influence the occurrence, severity or associated pathology of GVHD in the B10D2F1 murine GVHD model. 2) Isolate important loci on congenic strains. Identification of loci is of no value unless the function of those loci can then be investigated and the mechanism whereby allelic variation at those loci influences GVHD can be determined. In this project, a set of congenic strains will be created which will isolate the genes of interest and will be permanent tools with which the loci involved can be investigated. Additionally, a set of Mls congenics will be created in order to investigate the role of Mls antigens in influencing GVHD in murine models. 3) Analyze the role of individual loci in influencing GVHD using the congenic strains created in Aim #2.
