MOLECULAR ANALYSIS OF POLIOVIRUS NEURTRALIZING EPITOPES

脊髓灰质炎病毒疫苗的成功有力地影响了当前的 关于疫苗如何工作的概念。这些概念反过来又形成了 提出了许多战略的基本理论框架 疫苗开发和疫苗效力评估。然而，这些 在我们了解细胞免疫之前，概念就已经形成了 (CMI)回应，几乎没有直接信息来解释 个体免疫反应保护机体免受病毒感染的机制 疾病的发展。显然，对脊髓灰质炎病毒特异性体液的澄清 CMI的反应对于理解这些反应是如何进行的至关重要 保护宿主免受疾病侵袭。为了实现这些目标，具体的 目标如下： L。免疫反应的“解剖学”将以 确定辅助性T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部位和 描述病毒特异性T淋巴细胞群体的性质。 这些研究将检验T表位的选择是否受到 层序环境与中和是否识别 抗原位置将为识别T表位提供一般标准 富裕地区。此外，T淋巴细胞亚群的亚群 在诱导反应中的存在将被确定。类似的研究将 在病毒感染后在脊髓灰质炎病毒允许转基因小鼠(TgPVR)中进行 感染。结果将与在正常情况下观察到的结果进行比较 以确定C57BL/6小鼠的免疫反应是否相同 易感宿主与不敏感宿主。 2.体液反应和CMI反应在疾病中的体内作用 将使用批量脊髓灰质炎病毒确定生产和/或宿主保护 特定的T细胞群体、确定的特异性的T细胞克隆以及 具有明确特异性的单抗。收养转让和 被动免疫研究将在实验感染的患者中进行 脊髓灰质炎病毒允许转基因小鼠。这些研究将考察 T和B淋巴细胞在病毒清除、病毒传播和免疫调节中的相对作用 病理和最终的宿主保护。 病毒感染或感染引起的免疫反应的特征 疫苗接种对于了解疾病的分子基础是必要的。 尽管脊髓灰质炎病毒引起的体液反应已被广泛 由该实验室和其他实验室研究的细胞介导的免疫反应 (CMI)仍然相对不具特征。建议的目的是 研究的目的是开发更详细的分子描述 脊髓灰质炎病毒特异性CMI应答及其体内作用的研究 以及疾病保护中的体液反应。

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.