B7 COSTIMULATION RESPONSE TO EXTRACELLULAR BACTERIA

描述(改编自申请者摘要)：感染 胞外，多糖(PS)包裹的细菌是主要的 美国发病率和死亡率的来源。抗生素耐药性的增加 对这些病原体，使其更多地通过免疫治疗手段进行控制 令人信服。PS和蛋白质特异性免疫球蛋白的诱导在 对这些细菌的免疫力。初步结果，使用模型革兰氏阳性 胞外细菌肺炎链球菌(菌株R36A)表明 对R36A的PS和蛋白质特异性体液反应都依赖于T细胞 和B7配体依赖。调节B7配体相互作用具有治疗作用 改变正在进行的免疫反应和疫苗的可能性 发展，但很少有研究考察这些相互作用的作用 在T细胞依赖的免疫反应期间对细菌病原体。 该提案将研究B7交互在初选和 Memory Ig对R36A的PS和蛋白质成分的同型反应。CD28和 CTLA-4的功能将用基因缺陷小鼠和阻断 抗体的工作假设是这些分子是不同的 调节抗PS和抗蛋白质反应的进程，它们 可能是修改这种体内免疫反应的有用靶点，既在 初始阶段和免疫后。B7-1的个体作用 和B7-2，以及提供B7-1与 B7-2介导的共刺激作用将通过过继转移进行鉴定 在基因缺陷小鼠身上进行的实验。这些实验将提供 B7-1与B7-2阻断差异的机制探讨 影响R36A响应。 因此，这些研究将探讨B7介导的作用机制。 共刺激在调节对完全性免疫反应中的作用 活体内的胞外细菌，并可能为另一种 控制这些病原体的免疫治疗方法。

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. These studies will thus examine the mechanism of action of B7-mediated costimulation in regulating a humoral immune response to an intact extracellular bacterium in vivo, and may provide the basis for an additional immunotherapeutic approach for the control of these agents.