Somatic Diversification of Immunoglobulin Genes in GALT

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DESCRIPTION (provided by applicant): The preimmune antibody repertoire plays an important role in immune protection because it is the initial repertoire that determines to which antigens an individual will respond. The forces that shape this repertoire however, are largely unknown and the goal of this project is to determine the extent to which intestinal microorganisms contribute to the preimmune antibody repertoire. In rabbits, the preimmune antibody repertoire is generated through a combination of Ig gene rearrangements in utero followed by somatic diversification of the Ig genes in gut-associated lymphoid tissues (GALT) between 3 and 6 weeks after birth. This somatic diversification of Ig genes is dependent on the intestinal micro flora. The goal of this project is to determine the mechanism by which the intestinal flora promotes stimulation of B cells and somatic diversification of Ig genes in GALT. The specific aims of this application are to: 1) Introduce individual bacterial species into a sterile GALT environment and identify an organism that induces B cell follicle formation and somatic diversification of Ig genes; 2) Use immunotoxins and soluble CTLA4 and CD4O to deplete T cell activity in vivo and determine if T cells are required for somatic diversification of Ig genes in GALT; 3) Develop transgenic rabbit with VH-truncated m-chain to determine whether the B cell receptor is required for GALT development and somatic diversification of Ig genes, and 4) Determine whether B cells are stimulated in GALT by antigen or a microbial superantigen, by using ELISA, in vitro stimulation assays and anti-hapten transgenic rabbits. These studies are important because they will begin to elucidate how commensal intestinal microflora affects the antibody repertoire and may be useful for designing mucosal vaccines.