IMMUNE INTERVENTIONS OF AGED GUT MUCOSAL T CELL DEFECTS

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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.