The purpose of this collaborative study is to investigate neonatal (D3) thymectomy (D3TX)-induced autoimmune oophoritis and epididymo-vasitis as models of human infertility: the former corresponding to idiopathic secondary amenorrhea, and the latter, to men with sperm granuloma and those with vasal constriction and focal orchitis. Immunopathologic studies will test the hypothesis that D3TX depletes gonad-specific suppressor T cells, whose thymic or post-thymic differentiation is antigen dependent; and that effector T cells, of which the differentiation is also antigen-dependent, emigrate from the thymus before day 3. Antigen-specific T cell response to ovarian antigens will be quantitated by T lymphocyte proliferation and interleukin 2 production. By studying ovarian antigen from mice of different ages, the ontogeny of immunogenic ovarian antigens will be determined. The disease-inducing and disease-suppressing properties of thymic cells from mice of days -4, -2, 0, 3 and 7 will be analyzed, with or without further clonal expansion, for their ability to adoptively transfer disease to neonates and to suppress disease in D3TX recipients. Clonal expansion will be achieved by stimulation with ovarian antigens in vitro, or in vivo in irradiated syngeneic recipients (with or without marrow-reconstitution or thymectomy). Next, prenatal or neonatal ovariectomized D3TX mice reconstituted with ovarian homogenates will be studied in order to determine antigen-dependency of effector and suppressor cell induction. Adoptive transfer of oophoritis to the syngeneic or allogeneic recipients will be studied with respect to possible involvement of donor and recipient Ia+ antigen-presenting cells, and hence for the requirement of MHC-restriction. To investigate the possibility that chronic epididymo-vasitis can lead to vasal constriction, sperm granuloma and infertility, the fertility capacity of 6-month old D3TX males will be studied by mating, and the results correlated with testicular histopathology. Endocrinologic studies will examine the hypothalamus-pituitary-testis axis of D3TX mice. Sham TX, D3TX and D7TX mice will be compared, before and after disease onset, for serum testosterone and gonadotropin levels; testicular receptors for LH and PRL; pituitary LH, FSH, PRL, GH, GnRH and dopamine receptors; and hypothalamic LHRH, tyrosine hydroxylase and somatostatin. For these studies, radioimmunoassay and immunocytochemistry will be employed.
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