EFFECTOR MECHANISMS OF MURINE GVHD

We have identified a new, heretofore undescribed class of lymphocytes with a novel CD4+8-3- phenotype. We find these cells in the skin and spleen of mice with graft versus host disease (GVHD), which is a lethal complication of bone marrow transplantation. Despite advances in immunobiology, our understanding of effector mechanisms of GVHD is unclear. We have developed a murine model of bone marrow transplantation in order to focus on the effector:target interactions during GVHD, particularly in the skin. Our studies demonstrate the presence of a previously unrecognized type of lymphocyte in affected GVHD organs. We have isolated this cell and injected it into the skin of secondary recipients, where it causes the lesion of GVHD skin damage. We have also created CD4+8-3- T cell hybridomas from the spleens of mice with GVHD in order to study these cells in vitro. With these preliminary studies as a basis, we propose to test the hypothesis that CD4+8-3- lymphocytes are important effector cells in GVHD. Our specific aims are: 1. To characterize critical mechanisms of action of effector cells in the skin during GVHD. 2. To characterize which lymphokines participate in damaging the skin during GVHD. 3. To determine the importance of CD4+8-3- lymphocytes in other models of GVHD. 4. To determine whether CD4+8-3- lymphocytes are of T cell lineage. We expect that insights from these murine models will increase our understanding both of GVHD effector mechanisms and of developmental abnormalities of cell-mediated immunity.