NUCLEAR TRANSCRIPTION FACTOR ROLE IN T CELL ACTIVATION AND DISEASE

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Nuclear transcription factors, NF- B (e.g. p52) family and I B (e.g. Bcl-3) family, play a critical role in the response of cells of the immune system. The in vitro activity of these proteins has been examined but their in vivo role had not been documented. Mice deficient in Bcl-3 and p52 were generated in order to address the vivo function of these proteins. Both Bcl-3-deficient and p52-deficient mice exhibited overlapping phenotypes in that they had defects in splenic microarchitecture, germinal center reactions, and humoral responses. At the same time, they each exhibited some unique characteristics. These finding demonstrate an in vivo function for these proteins, particularly in regard to B cell function. This group evaluates protocols for the reconstitution of hematopoietic and lymphoid lineage cells in patients who have received chemotherapy. A major impediment to reconstitution comes from graft vs host disease, in which T cells present in the donor graft react against the recipient. We also assess protocols designed for the treatment of autoaggressive immune diseases such as multiple sclerosis and arthritis. In these diseases, pathology is mediated by inflammatory immune responses and current strategies for the treatment of these diseases is directed at suppressing these inflammatory responses. An understanding of the intracellular mediators of these responses and the creation of animal models that reflect these processes, such as those used in this project, are essential for the development and testing of new therapies. Moreover, this research require an in depth knowledge of immunfluorescence, flow cytometry, and cytokine assays, techniques which are used by sponsors to assess their products and preclinical/clinical results.