This Program Project Grant seeks continued support for investigations into the biology of hematopoietic cell transplantation (HCT) and the translation of concepts to the clinic to improve the outcomes for patients with serious hematological malignancies. The overarching hypothesis of this proposal is that cellular components are critical to transplantation biology and through the in depth understanding of the molecular and cellular events of discrete cell populations fundamental discoveries will be made which will have critical therapeutic implications. Although our clinical efforts are focused on patients with hematological malignancies the concepts developed have broad implications in many fields of biology and medicine extending to patients with malignancies, autoimmune disorders and undergoing solid organ transplantation. The investigators will focus on the major cellular components of the hematopoietic and immune systems including hematopoietic stem and progenitor cells, B, T, natural killer (NK), NK-T, regulatory and dendritic cell populations. The major events in HCT including stem cell engraftment, graft vs host disease (GVHD), graft vs tumor (GVT) reactions and immune reconstitution will be studied in detail. Clinical studies range from exploratory phase I/I I clinical trials to phase III definitive examinations of treatment strategies. We will build upon our success in the prior funding period where we have developed a novel non-myeloablative preparative regimen which results in consistent donor specific engraftment with maintained GVT effects with markedly reduced risk of GVHD. We will also extend the use of cellular products studied within the context of this Grant and successfully translated to the clinic. The proposal consists of 8 Projects and 4 supportive Cores which provide critical functions of administration, biostatistics and data management, molecular pathology and novel cellular imaging strategies and GMP laboratory services for cell product development and sample distribution. As a whole this integrated group of investigators will focus their efforts on critical issues of hematopoietic cell transplantation and cellular based therapeutics.