IMMUNE INTERVENTIONS OF AGED GUT MUCOSAL T CELL DEFECTS

本研究建议的目的是首先调查 年龄相关的肠道相关粘膜免疫变化 响应肠道微生物Ag的功能。 特别重点 将对年龄相关的Ag特异性粘膜变化进行研究 免疫调节功能，即，T细胞-B细胞相互作用 发生在肠相关淋巴组织（GALT）（Peyer’s 补丁（PP）和肠系膜淋巴结（MLN），这有助于， 抑制或对比抑制银和类的生产， 特异性免疫球蛋白（IG），特别是B细胞的IgA。 上 根据我们最近对年龄相关免疫调节T细胞的研究， 在PP中的细胞活动，将特别注意Ag- 老年人GALT特异性抑制-诱导T细胞活性 小鼠 在这些研究中，我们将使用几种原生质Ag 从肠道致病分枝杆菌，分枝杆菌 副结核病 与年龄相关的免疫功能下降的一个组成部分是 促进生长的淋巴因子的产生减少 白细胞介素2（IL-2）。 IL-2的施用，主要 在体外研究，似乎恢复某些免疫功能， 老年小鼠和人类。 第二，免疫学 IL-2的再生特性将在老年人中进行体内评估。 GALT。 第三，我们将进一步扩大上述药理学 用IL-2进行操作以沿着过继免疫细胞疗法 淋巴因子的体内给药。 在这一系列的被动 细胞转移实验，GALT衍生的Ag特异性克隆 免疫调节性T细胞亚群，特别是Tsi细胞，将被 在相应的Ag存在下体外扩增， 然后被雇用。 这些克隆的T细胞将倾向于在 细胞转移后的GALT位点。 这些干预性的方法 到实验室中的局部（粘膜）免疫再生， 利用动物，将可能有助于开发新的 治疗方式，以老年人遭受的生活- 威胁胃肠道感染和恶性肿瘤。 的 通过本文提出的实验设计获得的信息 也将在进行更有效的肠内和 用疫苗进行肠胃外免疫， 老年人上述严重疾病的发展。

The aim of the present research proposal is first to investigate age-associated changes in gut-associated mucosal immune function in response to enteric microbial Ag. The particular focus will be on the study of age-related changes in Ag-specific mucosal immunoregulatory functions, i.e., T cell-b cell interactions occurring in gut associated lymphoid tissues (GALT) (Peyer's patches (PP) and mesenteric lymph nodes (MLN) which help, suppress or contrasuppress the production of Ag- and class- specific immunoglobulins (Ig), particularly IgA by B cells. On the basis of our recent studies on age-associated immunoregulatory T cell activities in PP, a special attention will be made to Ag- specific suppressor-inducer T (Tsi) cell activity in GALT of aged mice. In these studies, we will employ several protoplasmic Ag from an intestinal pathogenic mycobacterium, Mycobacterium paratuberculosis. One component of the age-related decline in immune functions is decreased production of the lymphokine that promotes the growth of T cells, interleukin 2 (IL-2). Administration of IL-2, mainly studied in vitro, appears to restore certain immune functions in aged mice and humans. Thus, second, immunologically rejuvenating properties of IL-2 will be assessed in vivo in aged GALT. Third, we will further extend the above pharmacologic manipulation with IL-2 to adoptive immunocytotherapy along with in vivo administration of the lymphokine. In this series of passive cell transfer experiments, GALT-derived Ag-specific cloned immunoregulatory T cell subsets, in particular the Tsi cell, will be expanded in vitro in the presence of the corresponding Ag and then be employed. These cloned T cells will tend to home at GALT sites after the cell transfer. These intervenient approaches to local (mucosal) immunologic rejuvenation in the laboratory, using animals, will potentially contribute to develop new therapeutic modalities to aged individuals suffering form life- threatening gastrointestinal infections and malignancies. The information obtained by the experimental designs proposed here will also be of value in conducting more efficient enteric and parenteral immunization with vaccines for protection against the development of the above mentioned serious diseases in the aged.