): This proposal outlines a 5 year plan for the candidate to develop the necessary skills and experience to become an independent investigator studying the alloimmunology of bone marrow transplantation. Dr. Shlomchik is board certified in Internal Medicine and Hematology, and is board eligible in Oncology. He has been in the sponsor's lab for 3 years studying Graft-vs.Host Disease (GVHD), T cell tolerance post alloBMT, and methods of gene transfer into human T cells. Chronic myelogenous leukemia (CML) is uniquely sensitive to T cell alloimmune therapies, yet the scientific basis for CML's remarkable susceptibility is unknown. Understanding the details of this anti-CML response, including the nature of antigen presentation, critical effectors, and factors that render CML cells vulnerable to immune attack, may facilitate the development of strategies to enhance alloimmune responses against other less immunogenic neoplasms. The identification of factors that render CML sensitive have been impeded by the absence of: 1) tools needed to isolate individual components of alloimmune responses; and 2) a relevant murine CML model. The first obstacle can now be approached using mice deficient in genes critical for antigen presentation and T cell effector function. For example, the applicants have exploited mice lacking the beta-2-microblobulin gene to demonstrate that radioresistant host cells are critical for initiating GVHD responses. The second problem has been addressed by a new CML murine model wherein bone marrow infected ex vivo with retrovirus expressing the bcr-abl fusion cDNA is transferred into irradiated syngeneic recipients. They will combine these approaches to determine: 1) the identity of anti-CML effectors; 2) the identity of antigen presenting cells in anti-CML responses, and 3) the roles of molecules accessory for target cell vulnerability such as Fas and TNF-R by establishing CML in mice genetically deficient in them. Dr. Shlomchik's sponsor, Dr. Emerson, is chief of the hematology and oncology section. He has a Ph.D. in immunology and was scientific director of the alloBMT program at the University of Michigan. He has launched a new alloBMT program at Penn and is committed to Dr. Shlomchik's development into an independent clinician scientist.
