I am applying for an Individual Research Career Award (""""""""K"""""""" series) in order to continue my training in immunology, particularly in experimental approaches to tolerance induction. My previous experience in immunology research has provided me with a solid foundation for this pursuit, and I believe that additional training under the guidance of a basic immunologist, Dr. Abul Abbas, will allow me to develop a fundamental understanding of immunology that will help me to develop into a productive independent investigator. My clinical and teaching duties in clinical transplantation will be limited, but will provide a clinical perspective that will guide my work. My interactions with Dr. Abbas, and another leading investigator in the study of immune tolerance, Dr. Jeffrey Bluestone, as well as the UCSF immunology community in general, will add immensely to my training and provide me with excellent role models. These interactions, along with outstanding institutional strength and support, will provide an ideal environment in which to mature as a scientist. My ultimate goal is to translate advances in basic immunology to improving the outcomes of solid organ as well as islet transplantation. Clinical organ transplantation remains limited by the problems of immune rejection and the complications of generalized immunosuppression. Recent advances in the understanding of T cell activation and downregulation have afforded new approaches to attaining the ideal of transplant-specific tolerance. A growing understanding of the biology of dendritic cells has lead to the concepts that dendritic cells are key regulators of tolerance, and that dendritic cells may be useful vehicles for the delivery of tolerogenic signals. Previous efforts to utilize dendritic cells for this purpose have been limited by the difficulty of genetically modifying these cells to study systematically the factors that determine the outcome of dendritic cell-T cell interactions. Using a novel, efficient gene transduction technique that we have developed, we hope to elucidate how the migration of dendritic cells affects the subsequent immune response, and how this may be manipulated to facilitate tolerance induction. We propose to study in depth how targeted delivery of dendritic cells expressing immunomodulatory genes affects allospecific T cells in vivo. We will subsequently examine how these modifications can be utilized to extend allograft survival.
