Studies in humans and animals have shown that prenatal-exposure to a synthetic estrogen hormone, diethylstilbestrol (DES), increases susceptibility to neoplastic and teratogenic abnormalities of reproductive tissues. Additional concerns have now been raised that women prenatally-exposed to DES are also susceptible to autoimmune diseases. Animal studies also document that estrogenic compounds have a marked effect on the immune system. For example, normal mice perinatally exposed to estrogen have atrophied thymus and develop autoimmunity. These mice have impaired ability to proliferate to T cell mitogens, which is a """"""""life long"""""""" defect suggestive of immunologic imprinting. Defects of T cells induced by DES may contribute to increased susceptibility to neoplastic, autoimmune or infectious diseases, tumors or infection. We hypothesize that exposure of fetuses to DES (at a critical stage of immune system development) may skew the T cell ontogeny. This may result in individuals with an impaired immune system. To test this hypothesis, we will focus our studies on the phenotype and function of T cells from offspring of pregnant mice injected with DES. Mice will be examined from fetal to senescent age to determine whether immunological changes are transient or permanent.
The aims of this proposal are;
Aim I : To delineate the intrathymic T cell ontogeny in mice prenatally-exposed to DES. The DES- sensitive stage in T-cell ontogeny will be determined by using monoclonal antibodies to developmentally-regulated surface markers by flow cytometry. Further, apoptosis of thymocytes will be determined and correlated with expression of fas, an apoptotic marker gene.
Aim I l: To dissect defects in splenic T cell proliferation in prenatal DES-exposed mice.. T cells will be analyzed for alterations in: numbers of splenic CD3+/alphaBeta TCR+ cells, expression of activation markers, response to cytokines (eg. IL-2, IL-12), intracellular Ca++ levels and response to co-stimulatory signals.
Aim III : To analyze the significance and nature of DES-induced T cell defects by determining whether: (i) augmented IgG autoantibodies to dsDNA and cardiolipin (a phospholipid) in estrogen- exposed mice is a consequence of altered help from spleen or liver T cells; (ii) there is an imbalance of Th1 and Th2 subsets. A shift towards Th2, may explain increased expression of autoantibodies or diminished T- cell mediated immunity; (iii) alterations in T cell response in vivo to Th1-inducer antigens (B.abortus). It is anticipated that these studies will provide new information on the hazards of development of fetuses in a hyperestrogenic maternal environment, i.e., potential for the genesis of birth defects of T cells.
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