B7 COSTIMULATION RESPONSE TO EXTRACELLULAR BACTERIA

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DESCRIPTION (Adapted from the Applicant's Abstract): Infections with extracellular, polysaccharide (PS)-encapsulated, bacteria represent a major source of morbidity and mortality in the U.S. Increasing antibiotic resistance to these agents, makes their control by immunotherapeutic means more compelling. Induction of PS- and protein-specific Ig play major roles in immunity to these bacteria. Preliminary results, using a model gram-positive extracellular bacterium, Streptococcus pneumoniae (strain R36A), indicate that both PS- and protein-specific humoral responses to R36A are T cell-dependent and B7 ligand-dependent. Modulating B7 ligand interactions has therapeutic potential for modifying the ongoing immune response and for vaccine development, yet few studies have examined the role of these interactions during the T cell-dependent immune response to bacterial pathogens. This proposal will examine the role of B7 interactions during primary and memory Ig isotype responses to the PS and protein components of R36A. CD28 and CTLA-4 function will be examined using genetically deficient mice and blocking antibodies with the working hypothesis that these molecules differentially regulate the progression of the anti-PS and anti-protein response and that they may be useful targets for modifying this in vivo immune response, both at the initiation stage and subsequent to immunization. The individual roles of B7-1 and B7-2 will also be examined, and the specific APCs that provide B7-1 vs. B7-2-mediated costimulation will be identified using adoptive transfer experiments in genetically deficient mice. These experiments will provide insight into the mechanism of why B7-1 vs. B7-2 blockade differentially influences the R36A response.