MOLECULAR ANALYSIS OF POLIOVIRUS NEURTRALIZING EPITOPES

脊髓灰质炎病毒中和表位的分子分析

• 批准号: 2003352
• 负责人: Marie Chow
• 金额: $ 16.23万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-12-01 至 1999-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2003352
• 关键词: B lymphocyte; cell population study; cellular immunity; cytotoxic T lymphocyte; genetically modified animals; helper T lymphocyte; host organism interaction; human subject; humoral immunity; laboratory mouse; laboratory rat; molecular pathology; monoclonal antibody; mutant; passive immunization; poliomyelitis vaccine; poliovirus; protein sequence; protein structure; tissue /cell culture; virus antigen

The success of the poliovirus vaccines have strongly influenced current concepts about how vaccines work. These concepts in turn have formed the present underlying theoretical framework for many of the strategies in vaccine development and vaccine efficacy assessment. However, these concepts were developed prior to our knowledge of cell-mediated immune (CMI) responses and little direct information exists that explains the mechanisms by which an individual's immune responses protects against disease development. Clearly, elucidation of poliovirus-specific humoral and CMI responses is critical to an understanding of how these responses protect the host against disease. To achieve these goals, the specific aims are the following: l. The "anatomy" of the immune response will be characterized by determining whether T helper and cytotoxic epitopes colocalize to previously determined poliovirus neutralizing antigenic sites and by characterizing the nature of the virus-specific T lymphocyte population. These studies will examine whether T epitope selection is influenced by the sequence environment and whether identification of neutralizing antigenic sites will provide general criteria for identifying T epitope rich regions. In addition, the subtypes of T lymphocyte populations present in the induced response will be determined. Similar studies will be performed in poliovirus-permissive transgenic mice (TgPVR) after viral infection. The results will be compared with that observed in normal C57BL/6 mice to determine whether immune responses are identical in susceptible vs. nonsusceptible hosts. 2. The in vivo roles of the humoral and CMI responses in disease production and/or host protection will be defined using bulk poliovirus specific T cell populations, T cell clones of defined specificities, and monoclonal antibodies of defined specificities. Adoptive transfer and passive immunization studies will be performed in experimentally infected poliovirus permissive transgenic mice. These studies will examine the relative roles of T and B lymphocytes in virus clearance, virus spread and pathology and ultimately host protection. Characterization of the immune response induced upon viral infection or vaccination is necessary to understanding the molecular basis of disease. Although the humoral response induced by poliovirus has been extensively studied by this and other laboratories, the cell-mediated immune response (CMI) has remained relatively uncharacterized. The aim of the proposed research is to develop a more detailed molecular description of the poliovirus-specific CMI response and to study the in vivo role of the CMI and humoral responses in disease protection.

脊髓灰质炎病毒疫苗的成功极大地影响了目前的 关于疫苗是如何工作的。这些概念反过来又形成了 目前的许多战略的基本理论框架， 疫苗开发和疫苗效力评估。但这些 在我们了解细胞介导的免疫之前， (CMI)答案和很少的直接信息存在，解释了 个体的免疫反应保护免受 疾病发展。很明显，脊髓灰质炎病毒特异性体液免疫的阐明 而CMI的反应对于理解这些反应是如何 保护宿主免受疾病侵害。为了实现这些目标，具体 目标如下： L.免疫反应的“解剖学”特征如下： 确定T辅助细胞和细胞毒性表位是否共定位， 先前确定的脊髓灰质炎病毒中和抗原位点， 表征病毒特异性T淋巴细胞群体的性质。 这些研究将检查T表位选择是否受到以下因素的影响： 测序环境和是否鉴定中和 抗原位点将提供鉴定T表位的一般标准 富有的地区。此外，T淋巴细胞群的亚型 将确定诱导反应中的存在。类似的研究将 在脊髓灰质炎病毒允许转基因小鼠（TgPVR）中进行， 感染结果将与正常对照组进行比较。 C57 BL/6小鼠，以确定免疫应答是否与C57 BL/6小鼠相同。 易感宿主和非易感宿主。 2.体液和CMI反应在疾病中的体内作用 将使用批量脊髓灰质炎病毒定义生产和/或主机保护 特异性T细胞群，确定特异性的T细胞克隆，和 确定特异性的单克隆抗体。过继转移和 被动免疫研究将在实验感染的 脊髓灰质炎病毒许可转基因小鼠。这些研究将审查 T和B淋巴细胞在病毒清除、病毒传播和 病理学和最终宿主保护。 病毒感染后诱导的免疫应答的表征或 接种疫苗对了解疾病的分子基础是必要的。 虽然脊髓灰质炎病毒诱导的体液反应已被广泛应用， 通过这个实验室和其他实验室的研究，细胞介导的免疫反应 (CMI)相对来说还没有被描述建议的目的 研究的目的是开发一种更详细的分子描述， 脊髓灰质炎病毒特异性CMI应答，并研究CMI的体内作用 和体液反应的作用。