Biography
Robert S. Negrin is a Professor of Medicine at Stanford University. He received his undergraduate degree from the University of California at Berkeley and his M.D. from Harvard Medical School. He performed his internship, residency and fellowship in Hematology at Stanford University. He joined the faculty at Stanford University in 1990 and was promoted to Associate Professor in 1997 and full professor in 2004. He has served as the President of the International Society of Cellular Therapy and will assume the presidency of the American Society of Blood and Marrow Transplantation in the year 2006. His research interests involve characterizing graft-versus-host and graft-versus-tumor reactions and developing cell-based therapeutics for the treatment of malignancies and other disorders. He is currently the Director of the Bone Marrow Transplant Program at Stanford University and Medical Director for the Stanford Cell Therapeutics Laboratory.
Abstract
Regulatory T Cells in Bone Marrow Transplantation
Regulation of the immune response holds great promise for the treatment of a variety of clinical conditions. In hematopoietic cell transplantation the transfer of immunity from donor to recipient is capable of curing malignancy in a reaction termed the graft vs tumor (GVT) effect. Equally potent and clinically dangerous is graft vs host disease (GVHD), which is the major limitation to successful allogeneic transplantation and limits the use of this treatment approach to patients with life threatening malignancies. Animal studies have clearly demonstrated that allogeneic hermatopoietic cell transplantation is capable of curing autoimmune disorders and enhances the survival of transplanted organs in the setting where GVHD can be controlled. Therefore, strategies, which are capable of controlling GVHD yet allow for GVT reactions, hold great promise in clinical medicine. In this proposal we will directly extend our recently discovered findings that a naturally present population of regulatory T cells with the defined cell surface phenotype of CD4+ CD25+ are capable of controlling GVHD in animal models across major histocompatibility barriers. Importantly, the Treg cells did not inhibit GVT effects. Further experimentation has demonstrated that the mechanism of this effect is due to the ability of the Treg to control proliferation of alloreactive conventional T cells which upon activation and expansion cause GVHD. In the presence of Treg alloreactive T cells still become activated which allows for GVT reactions, yet prevention of massive T cell expansion controls GVHD. An analogous population of human Treg cells with very similar properties with respect to cell surface phenotype and function can be found in the blood. In this proposal we will directly extend our bench results to the bedside where we will isolate, characterize and transplant highly defined populations of conventional and regulatory T cells. In the first Specific Aim, we will focus on the characterization and expansion of human Treg cells. We have developed a novel assay of cytotoxicity which will allow for the probing of effects of Treg cells on conventional T cell activation, expansion and cytotoxic function. We will explore the impact of freshly isolated and expanded Treg cells on the activity of conventional T cells in these assays and probe specific molecules using molecular and cellular biological techniques to explore mechanisms. In the second Specific Aim, we will directly extend these findings to the clinic where we will isolate pure populations of Treg cells with high speed cell sorting and pursue allogeneic transplantation in patients with malignancies. These studies will define both the biological and clinical activity of this unique population of T cells with immune regulatory function.