DENDRITIC AND T CELLS IN ANTI-BACTERIAL Ig RESPONSES

描述(申请人提供)：由胞外细菌引起的感染 继续构成一个重大的全球健康问题。这在很大程度上是由于 与不断出现的抗药性菌株有关。因此，存在着 迫切需要开发保护性疫苗。免疫是由以下因素调节的 抗细菌多糖(PS)和蛋白质的抗体。然而， 在体内调节抗PS和抗PS的参数知之甚少 对完整的胞外细菌的抗蛋白反应，尽管这样 这些信息与合理设计针对这些疾病的免疫疗法有关 探员们。 我们已经建立了一个体内模型系统来研究其作用机制。 抗PS和抗蛋白Ig亚型对完整免疫应答的诱导 肺炎链球菌。具体地说，免疫球蛋白同型反应 磷酰胆碱(PC)决定簇，存在于细菌细胞壁C-PS是 研究并比较了对细胞壁蛋白的体液反应， 肺炎球菌表面蛋白A(PSPA)。我们证明了最优诱导 抗PC和抗PSPA反应都需要CD4+TCR-a/b+T细胞 B7依赖的共刺激作用，尽管记忆不能产生诱导 PC特定的Ig。有趣的是，T细胞依赖的潜在机制 这两种反应是截然不同的。我们进一步证明树突状细胞(DC) 能否吞噬肺炎链球菌转移到幼鼠体内，诱导两者 抗PC和抗PSPA Ig反应，以及PSPA特异性记忆的形成。 本申请的总体目的是阐明 DC对完整的胞外细菌进行反应和处理以诱导 体内依赖T细胞的PC和PSPA特异性Ig亚型，并确定 不同形式的T细胞的潜在机制有助于刺激 这些相应的抗原特异性免疫球蛋白同型反应。具体来说，我们将 利用一些体外和体内模型系统来确定1) 调节DC激活和抗原提呈的参数 R36A，2)DC子集的相对贡献，以及3)DC的作用 细胞因子和辅助分子，包括CD40、MHC 11和Toll样分子 感受器。在此背景下，4)直流刺激的不同要求 抗PC与抗PSPA反应的T细胞帮助将是 下定决心。 这些数据将是第一个建立起中介的详细参数 一种针对完整病毒的生理性抗原特异性体液免疫反应 胞外细菌，包括描绘基本的 多糖类和蛋白质特异性免疫球蛋白同型反应的差异。

DESCRIPTION (provided by applicant): Infections due to extracellular bacteria continue to pose a significant global health problem. This is due in large part to the continual emergence of antibiotic-resistant strains. Hence, there exists an urgent need for development of protective vaccines. Immunity is mediated by antibodies to the bacterial polysaccharides (PS) as well as proteins. However, little is known regarding the parameters that mediate in vivo anti-PS and anti-protein responses to intact extracellular bacteria, although such information has relevance to the rational design of immunotherapies for these agents. We have established an in vivo model system for investigating the mechanism of induction of anti-PS and anti-protein Ig isotypes in response to intact Streptococcus pneumoniae. Specifically, the Ig isotype response to the phosphorylcholine (PC) determinant, present on the bacterial cell wall C-PS is studied and compared to the humoral response to a cell wall protein, pneumococcal surface protein A (PspA). We show that induction of optimal anti-PC and anti-PspA responses both require CD4+TCR-a/b+ T cells and B7-dependent costimulation, although memory fails to develop for induction of PC-specific Ig. Of interest, the mechanisms underlying the T cell-dependence of these two responses are distinct. We further show that dendritic cells (DCs) can phagocytose S. pneumoniae upon transfer into naive mice, induce both anti-PC and anti-PspA Ig responses, and the formation of PspA-specific memory. The general aims of this application are to elucidate the mechanisms by which DCs respond to and process an intact extracellular bacterium for induction of both T cell-dependent PC- and PspA-specific Ig isotypes in vivo, and determine the mechanisms underlying the distinct forms of T cell help that stimulate these respective antigen-specific Ig isotype responses. Specifically, we will utilize a number of in vitro and in vivo model systems to determine 1) the parameters that regulate DC activation and antigen presentation in response to R36A, 2) the relative contribution of DC subsets, and 3) the role of DC cytokines and accessory molecules, including CD40, MHC class 11, and Toll-like receptors. In this context, 4) the differential requirements for DC stimulation of T cell help for the anti-PC versus the anti-PspA response will be determined. These data will be the first to establish the detailed parameters that mediate a physiological antigen-specific humoral immune response to an intact extracellular bacterium, including the delineation of the fundamental differences between polysaccharide and protein-specific Ig isotype responses.