B Cell Related Prophylaxis and Therapeutics

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Specific antibody to biological weapons and agents of bioterrorism can be developed into a powerful component of our defensive arsenal. This section of the RCE application proposes to develop novel strategies to harness the potential of humoral and cell-mediated immunity against select agents of biological warfare. The section includes passive and active immunization-based approaches, which are complementary solutions to the problem of mobilizing the immune response. Passive immunization is currently the only means of providing immediate immunity to protect susceptible individuals at risk for biological warfare. However, despite over a century of study we still cannot predict the relationship between antibody structure, specificity, affinity and efficacy. The passive immunization component is focused on three select agents, Bacillus anthracis, Staphylococcal aureus enterotoxin, and West Nile virus and has three aims: 1) To produce neutralizing (murine and human) monoclonal antibodies to anthrax toxin protein components, S. aureus enterotoxin, and West Nile virus envelope; 2) To identify the antibody attributes necessary for optimal toxin and viral neutralizing activity; 3) To generate very high affinity neutralizing of activation induced deaminase (AID). Active immunization can make the host immune and has the advantage that it provides long lasting protection. The active immunization component is focused on two select agents: Yersinia pestis and Bacillus anthracis and has three specific aims: 1) To develop potent stimulatory function for T cells and B cells by identifying dendritic cell (DC) receptors that lead to more efficient uptake and presentation of vaccine antigens in vivo, as well as adjuvants that mature DCs including DC subsets; 2) To manipulate the marginal zone macrophages which contains specialized subsets of macrophages and DCs to elicit T cell independent antibody responses; 3) To identify new chemical compounds that stimulate a distinct toll-like receptor, RP-105, selectively expressed by B. cells. We anticipate that the proposed studies will lead to antibodies for therapeutic use, a better understanding of the relationship of antibody structure and function, and novel approaches to vaccination that exploit recent advances in our understanding of dendritic cell, macrophage and B cell biology.