Project: Research project

Project Details


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.
Effective start/end date12/31/8912/31/02