B7 COSTIMULATION RESPONSE TO EXTRACELLULAR BACTERIA

描述（改编自申请人的摘要）： 胞外多糖（PS）包裹的细菌代表了 在美国发病率和死亡率的来源增加抗生素耐药性 使其通过免疫手段的控制更加 引人注目。PS和蛋白特异性IG的诱导在 对这些细菌的免疫力。初步结果，使用革兰氏阳性 细胞外细菌肺炎链球菌（菌株R36 A）表明， 对R36 A的PS特异性和蛋白特异性体液应答都是T细胞依赖性的 和B7配体依赖性。调节B7配体相互作用具有治疗性 改变正在进行的免疫反应和疫苗的潜力 发展，但很少有研究探讨了这些相互作用的作用， 在对细菌病原体的T细胞依赖性免疫应答期间。 本提案将研究B7相互作用在初级和 记忆IG同种型对PS和R36 A蛋白组分的应答。cd 28和 将使用遗传缺陷小鼠和阻断来检查CTLA-4功能 抗体的工作假设，这些分子差异 调节抗PS和抗蛋白反应的进展， 可能是用于修饰这种体内免疫应答的有用靶点， 接种后和接种后。B7-1的个人角色 和B7-2也将被检查，并提供B7-1与B7- 2的特异性APC。 将使用过继转移鉴定B7-2介导的共刺激 基因缺陷小鼠的实验。这些实验将提供 深入了解B7-1与B7-2阻断差异的机制 影响R36 A响应。

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.