DENDRITIC AND T CELLS IN ANTI-BACTERIAL Ig RESPONSES

树突状细胞和 T 细胞在抗菌 Ig 反应中的作用

基本信息

批准号：
6870301
负责人：
CLIFFORD M SNAPPER
金额：
$ 25.94万
依托单位：
HENRY M. JACKSON FDN FOR THE ADV MIL/MED
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-04-01 至 2006-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6870301
关键词：
CD40 molecule MHC class II antigen Streptococcus pneumoniae antibacterial antibody antibody formation antigen presentation bacterial antigens bactericidal immunity cellular immunity cytokine dendritic cells helper T lymphocyte laboratory mouse protein biosynthesis tissue /cell culture

项目摘要

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.

描述（由申请人提供）：细胞外细菌引起的感染继续构成重大的全球健康问题。这很大程度上是由于导致抗生素耐药菌株的不断出现。因此，存在迫切需要开发保护性疫苗。免疫是通过针对细菌多糖 (PS) 以及蛋白质的抗体。然而，关于介导体内抗PS和介导的参数知之甚少对完整细胞外细菌的抗蛋白反应，尽管这样这些信息与免疫疗法的合理设计相关代理。我们建立了体内模型系统来研究其机制诱导抗 PS 和抗蛋白 Ig 同种型以响应完整肺炎链球菌。具体而言，Ig 同种型对磷酸胆碱 (PC) 决定簇，存在于细菌细胞壁 C-PS 上研究并与细胞壁蛋白的体液反应进行比较，肺炎球菌表面蛋白 A (PspA)。我们证明了最优的归纳抗 PC 和抗 PspA 反应均需要 CD4+TCR-a/b+ T 细胞，并且 B7 依赖性共刺激，尽管记忆未能发展以诱导 PC 特异性 Ig。有趣的是，T 细胞依赖性的潜在机制这两种反应是截然不同的。我们进一步表明，树突状细胞（DC）转移到幼鼠体内后可以吞噬肺炎链球菌，诱导抗PC和抗PspA Ig反应，并形成PspA特异性记忆。本申请的总体目标是阐明其机制 DC 响应并处理完整的细胞外细菌以诱导体内 T 细胞依赖性 PC 和 PspA 特异性 Ig 同种型，并确定 T 细胞不同形式的潜在机制有助于刺激这些各自的抗原特异性 Ig 同种型反应。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 激活和抗原呈递的参数 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 类和 Toll 样受体。在这种情况下，4）直流刺激的不同要求 T 细胞对抗 PC 与抗 PspA 反应的帮助将是决定。这些数据将首先建立调解的详细参数对完整抗原的生理学抗原特异性体液免疫反应细胞外细菌，包括基本的划分多糖和蛋白质特异性 Ig 同种型反应之间的差异。