REOVIRUSES AND PROBES OF MUCOSAL IMMUNE RESPONSES

呼肠孤病毒和粘膜免疫反应探针

• 批准号: 2671875
• 负责人: JOHN J CEBRA
• 金额: $ 13.9万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-08-01 至 2002-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2671875
• 关键词: B lymphocyte; Orthoreovirus; Peyer's patches; SCID mouse; cellular immunity; cytotoxic T lymphocyte; disease /disorder model; fluorescence microscopy; gastrointestinal infection; gut associated lymphoid tissue; helper T lymphocyte; humoral immunity; immunocytochemistry; immunoglobulin A; immunoglobulin isotypes; intestinal mucosa; laboratory mouse; mucosal immunity; natural killer cells; plaque assay; respiratory infections; secretory immune system

This ongoing research program, in its eleventh year, has utilized respiratory/enteric orphan (REO) viruses as model probes of the mucosal immune system. Thusfar we have confined our studies to the gut and liver of various mouse hosts: immunocompetent or severe-combined immunodeficient neonates and adults. We have made a number of original fundamental findings concerning the host's mucosal immune response in the gut: especially ato elucidate the role of the Peyer's patch microenvironment in mediating preferred isotype switching of B cells to IgA (SecretaryAb) expression and in generating cytotoxic T cells (CTLs) that accumulate in intraepithelial spaces to contain enteric virus infections in the gut. Our studies have provided the functional bases for a 'cellular mucosal immune system' including both natural killer cells and cytotoxic T cells. We now propose to use reoviruses - which also display a tropism for respiratory epithelial cells - to address certain major, unresolved, fundamental questions concerning the 'mucosal' component of the immune system which functions in the respiratory tract (RALT). We plan to use assays which we have originally developed - the T dependent, clonal B cell microculture and organ fragment cultures for mucosal tissues - and the limiting dilution analyses for CTLs plus MAbs vs. mucosal 'homing' receptors, in these attempts: l) to determine whether RALT contains inductive sites analogous to those in Peyer's patches where preferred isotype switching to IgA occurs; 2) to assess whether CTLs with 'mucosal' homing propensities can be generated in the gut or RALT, and whether these can contribute effective protection to the respiratory tract; and 3) whether effective 'cross-priming' between gut and RALT can occur. The results of these analyses should be extremely relevant for the development of efficacious vaccines vs. respiratory pathogens.

这项正在进行的研究计划已进入第十一年，利用了 呼吸道/肠道孤儿（REO）病毒作为模型探针 粘膜免疫系统。 到目前为止，我们的研究仅限于 各种小鼠宿主的肠道和肝脏：免疫活性或 严重联合免疫缺陷的新生儿和成人。我们有 做出了一些有关的原始基本发现 宿主肠道内的粘膜免疫反应：尤其是ato 阐明派尔氏淋巴结微环境在 介导 B 细胞向 IgA 的优先同种型转换 (SecretaryAb) 表达和生成细胞毒性 T 细胞 （CTL）积聚在上皮内空间以容纳肠 肠道内的病毒感染。 我们的研究提供了 “细胞粘膜免疫系统”的功能基础包括 自然杀伤细胞和细胞毒性 T 细胞。我们现在建议 使用呼肠孤病毒——它也表现出对呼吸道的趋向性 上皮细胞 - 解决某些主要的、未解决的、根本性的问题 关于免疫“粘膜”成分的问题 在呼吸道中发挥作用的系统（RALT）。我们计划 使用我们最初开发的检测方法 - T 依赖性克隆 B 细胞微量培养和器官片段培养 用于粘膜组织 - 以及 CTL 的有限稀释分析 加上单克隆抗体与粘膜“归巢”受体的比较，在这些尝试中：l) 确定 RALT 是否含有类似于以下的诱导位点 派尔氏斑中首选同种型转换为 IgA 的患者 发生； 2) 评估CTL是否具有“粘膜”归巢能力 倾向可以在肠道或 RALT 中产生，并且是否 这些可以有效保护呼吸道； 3) 肠道和 RALT 之间是否有效“交叉启动” 可能会发生。这些分析的结果应该是非常 与开发有效疫苗相关 呼吸道病原体。