The cytolytic T lymphocyte (CTL) plays a central role in allograft rejection. Matching prospective donors and recipients at the HLA-A,B and DR loci has significantly prolonged allograft survival. Despite massive immunosuppression, however, many kidney allografts are still rejected. This is not surprising since 1) we have not yet identified all important target alloantigens, especially antigens expressed by biologically relevant target cells, such as vascular endothelium, and 2) real insight into the CTL-target interaction is not possible without a molecular understanding of the structures involved. Although the ultimate goal of this project is the development of specific modes of immunosuppression capable of promoting long term allograft survival with minimal side effects, the definition of the structure and function of cell surface molecules involved in the CTL response represents an essential step toward this goal. The approach we propose is based on 1) the generation of long term human allogeneic CTL lines and clones, and 2) the development of monoclonal antibodies which bind to target or effector surface antigens and block cytolysis. Together these reagents will be used for the biochemical and molecular characterization of these structures and may prove useful as immunotherapeutic agents in organ transplantation.
