The human syndrome of acquired immune deficiency (AIDS) results from infection with a retrovirus which has receptor-mediated tropism for T cells immune system. Development of effective anti- viral therapies is currently in progress. However, it is clear that such therapy must be complemented by efforts to regenerate immune function which has been destroyed by the virus. Since the thymus is a major site of involvement in AIDS and is the location of proliferation and maturation of functional T cells, regeneration of thymus function will be an important component of effective therapy for AIDS. The recent demonstration of receptors for androgens within thymocyte along with the well-recognized role of androgens in thymic involution suggest that androgens may exert suppressive effects on thymocyte maturation; attenuation of these effects might facilitate reconstitution of immune competence. The purpose of this proposal is to investigate effects of androgenic hormones on the proliferation and differentiation of developing thymocyte. A murine model of androgen resistance (testicular feminization; Tfm/Y) the result of a single gene mutation coding for defective androgen receptor offers the opportunity to study receptor-mediated effects of androgens on the thymus. Preliminary results indicate that Tfm/Y mice have large thymuses containing up to 100 times the number of thymocyte seen in age-matched control mice. These large thymuses also produce increased levels of interleukin-2 (IL-2), an important mediator of thymic growth. Treatment of Tfm/Y mice with exogenous androgen receptor mediates thymic growth and thymocyte proliferation and that the mechanism of this effect may involve IL-2. The purpose of this proposed work is: (1) to identify the target cells for androgens in the thymus; (2) to determine whether androgen-induced effects on the thymus involve production of or response to IL-2> These studies will utilize monoclonal antibodies to thymocyte surface markers, which are used with flow cytometry and cell sorting to identify and select for phenotypic subsets of thymocyte. In addition, a recently protein in intact cells. With these approaches it will be possible to determine which thymocyte contain androgen receptors, which subpopulations are expanded in the Tfm/Y thymus and which subpopulations are depleted in androgen-induced thymic involution. Functional studies of IL-2 will examine production of the and response to this lymphokine, as well as expression of the IL-2 receptor on target thymocyte. Correlations with thymus size, androgen receptor content and phenotypic markers will be analyzed to determine the relationship between these factors in the expression of thymus function. These findings will have implications for approaches to reconstitution of the immune system in AIDS.
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