DENDRITIC AND T CELLS IN ANTI-BACTERIAL Ig RESPONSES

描述（由申请人提供）：细胞外细菌引起的感染 继续构成严重的全球健康问题。这在很大程度上是由于 不断出现的抗药性菌株。因此，存在 迫切需要研制保护性疫苗。免疫是由 细菌多糖（PS）以及蛋白质的抗体。然而，在这方面， 关于介导体内抗PS的参数知之甚少， 抗蛋白质反应完整的细胞外细菌，虽然这种 这些信息与合理设计免疫疗法有关， 剂. 我们已经建立了一个体内模型系统，用于研究 诱导抗PS和抗蛋白IG同种型应答完整的 肺炎链球菌。具体地，IG同种型对免疫球蛋白的应答是由免疫球蛋白的免疫球蛋白的特异性决定的。 磷酸胆碱（PC）决定簇，存在于细菌细胞壁C-PS上， 研究并与对细胞壁蛋白质的体液反应进行比较， 肺炎球菌表面蛋白A（PspA）。我们表明，诱导的最佳 抗PC和抗PspA应答都需要CD 4 + TCR-α/B+ T细胞， B7依赖性共刺激，虽然记忆未能发展为诱导 PC特异性IG。感兴趣的是，T细胞依赖性的潜在机制， 这两种反应截然不同。我们进一步表明，树突状细胞（DC） 能吞噬S.在转移到未处理小鼠中后， 抗PC和抗PspA IG应答，以及PspA特异性记忆的形成。 本申请的总体目的是阐明 DC响应并处理完整的细胞外细菌以诱导 T细胞依赖性PC和PspA特异性IG同种型，并确定 不同形式的T细胞帮助刺激的机制 这些各自的抗原特异性IG同种型应答。具体来说，我们将 利用许多体外和体内模型系统来确定1） 调节DC活化和抗原呈递的参数 R36 A，2）DC亚群的相对贡献，和3）DC的作用 细胞因子和辅助分子，包括CD 40、MHC 11类和Toll样 受体。在这种情况下，4）直流电刺激的不同要求 T细胞对抗PC与抗PspA应答的帮助将是 测定 这些数据将是第一个建立详细的参数， 一种生理抗原特异性体液免疫反应， 细胞外细菌，包括基本的划定 多糖和蛋白特异性IG同种型应答之间的差异。

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.