application): The project has the following specific aims. (1) To determine whether the decreased diversity of the B cell repertoire in old mice results from the impaired development of a diverse repertoire in the central (bone marrow) and/or peripheral lymphoid (spleen and lymph nodes) tissues. They will use a novel PCR-based method to measure the heterogeneity of Ig CDR3 sizes to assay the diversity of the B cell repertoire and the appearance of clonal B cell populations in 3, 12, and 18 month old mice. They will also analyze the frequency of somatic mutations in an anti-H-2 antibody expressed as a transgene in RAG-1 deficient mice given syngeneic t cells from 3,12, and 18 month old mice. Finally, they shall determine the immunological consequences of monoclonal B cell expansions observed in old mice on the immune response. (2) To develop strategies to overcome the constraints in B cell development and somatic mutation in old mice. They will test the capacity of an immunoglobulin transgene, and inducible RAG genes to normalize B cell development in old mice. They will also determine whether T cells from young mice or TCP-17 can overcome the reported impaired capacity of T cells from old mice to support somatic mutation of transgene in a RAG-deficient environment. Finally, they will test the capacity of TCP-17 to increase RAG gene expression. VDJ rearrangement as well as the decreased rate of generating peripheral B cells in old mice.
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