This proposal details a five year training program for the applicant's transition from research investigator to independent investigator. The principal investigator has completed doctoral training in molecular immunology and post-doctoral training in molecular embryology, and now continues his training in transplant immunology. The present training emphasizes mechanisms of transplantation tolerance. James Markmann MD, PhD will mentor the scientific development of the principal investigator. Dr Markmann is a recognized leader in the field of transplantation research. He has trained numerous young scientists including research fellows and graduate students. An advisory committee of three well-recognized scientists from the institution's basic immunology community will provide necessary scientific and professional guidance. The Department of Surgery at the University of Pennsylvania provides an excellent environment for training research investigators and has a long history of transitioning them into independent investigators. The environment combines basic exploratory research as well as direct clinical applications for discovery. The research focuses on capitalizing on the unique properties of regulatory T cells (Tregs) to generate allograft tolerance. Specifically, our thesis is that rendering Tregs nonfunctional by inflammatory signals is a standard mechanism by which the immune system promotes initiation of an immune response. We base this on preliminary data suggesting that in the setting of allogeneic organ transplantation, innate inflammatory signals accompanying the procedure of organ transplantation interfere with the function of Tregs by triggering of the glucocorticoid-induced TNFR family-related gene (GITR) by its ligand (GITRL). Moreover, our preliminary data demonstrate that blockade of GITR triggering results in long-term skin allograft survival that is Treg-dependent. Thus we propose to delineate the mechanisms underlying the beneficial impact of GITR blockade on transplantation tolerance and to evaluate whether targeting this receptor-ligand pair can be exploited for therapeutic benefit in standard transplant tolerance models. First, we will assess the scope of the benefit derived from targeting GITR-GITRL employing a panel of transplantation tolerance models. Second, we will characterize the immunological mechanisms, cellular and molecular, by which Treg suppressor activity is augmented through disruption of GITR-GITRL interaction in vivo. A state of transplantation tolerance without the need for maintenance immunosuppressive therapy remains an elusive goal for immunobiologists. Our research focuses a novel and potentially clinically relevant approach to this end.
