IMMUNE INTERVENTIONS OF AGED GUT MUCOSAL T CELL DEFECTS

本研究提案的目的首先是调查 肠黏膜免疫功能的增龄性变化 对肠道微生物Ag作出反应的功能。特别关注的焦点 将研究与年龄相关的Ag特异性粘膜的变化 免疫调节功能，即T细胞与b细胞的相互作用 发生于肠道相关淋巴组织(GalT)(Peyer‘s 补片(PP)和肠系膜淋巴结(MLN)有助于， 抑制或相反抑制银离子和类银离子的产生 特异性免疫球蛋白(Ig)，尤其是B细胞的IgA。论 我们最近对年龄相关免疫调节T细胞的研究基础 在PP中的细胞活动，将特别注意Ag- 老年人高尔特特异性抑制诱导T细胞活性的研究 老鼠。在这些研究中，我们将使用几种原生质银 来自肠道致病分枝杆菌分枝杆菌 副结核。 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 T细胞中，白介素2(IL-2)。白介素2的应用，主要是 在体外研究，似乎恢复了某些免疫功能 老化的老鼠和人类。因此，第二，在免疫学上 IL-2的返老还童特性将在老年人体内进行评估 高尔特。第三，我们将进一步推广上述药理作用 IL-2对过继免疫细胞治疗的调控作用 淋巴因子的体内给药。在这一系列的被动中 细胞转移实验，GALT来源的银特异性克隆 免疫调节T细胞亚群，特别是TSI细胞，将 在相应的银存在下体外扩增 那就被雇佣吧。这些克隆的T细胞将倾向于在 细胞转移后的高尔特部位。这些介入的方法 到实验室的局部(粘膜)免疫复壮， 利用动物，可能有助于开发新的 对患有生命的老年人的治疗方式- 威胁到胃肠道感染和恶性肿瘤。这个 通过这里提出的实验设计获得的信息 也将在进行更有效的肠道和 用疫苗进行肠外免疫，以预防 上述严重疾病在老年人中的发展。

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.