DESCRIPTION (provided by applicant): The objective of the Program Grant is to understand the cellular and molecular basis of the induction of tolerance to allogeneic hematopoietic cell and organ transplants. The Program Project has one clinical project (Project 1) (S. Strober, Leader) that will attempt to induce persistent mixed chimerism and tolerance in recipients of related and unrelated HLA mismatched kidney transplants after conditioning with total lymphoid irradiation (TLI) and anti- thymocyte globulin (ATG). Project 2, (R. Negrin, Leader) will study the prevention and regulation of GVHD by the interactions between donor NKT cells and Treg cells after hematopoietic cell transplantation. Project 3, (E. Engleman, Leader) will study the role of recipient dendritic cell (DC) subsets that interact with recipient NKT cells to promote tolerance and chimerism after conditioning. Core A (S. Strober, Leader) will provide administrative and biostatistical support for all investigators. Core B (Scientific Core, E. Engleman Leader) will provide novel technology including CyTOF analysis of immune cell subset staining of up to 40 receptors simultaneously, gene expression changes in DCs, and/or high throughput sequencing of TCR genes to analyze the T cell clonal repertoire in humans and mice after tolerance induction. The preclinical models are designed to provide insights into basic biology of immune regulatory cells that can be applied to the immune monitoring and treatment of patients enrolled in the tolerance protocols. PROJECT 1 - TLI AND ATG CONDITIONING FOR COMBINED KIDNEY AND BLOOD STEM CELL TRANSPLANTATION (STROBER, SAMUEL)