Colorado PROFILES, The Colorado Clinical and Translational Sciences Institute (CCTSI)
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Substantial evidence exists supporting a role for maternal-fetal immune interactions in mediating a wide variety of reproductive complications, including infertility, recurrent miscarriage, preeclampsia, intrauterine growth retardation, and preterm birth. These problems entail substantial maternal and neonatal morbidity and mortality. The studies proposed herein are intended to enhance the understanding of the maternal-fetal immune relationship by focusing on the description of both phenotype and function of decidual T lymphocytes in a murine model. Circumstantial evidence for T cell involvement in gestation comes from numerous studies detailing changes in T cell subsets and the overall T population during gestation. More direct evidence of T cell involvement in pregnancy is presented here in the form of preliminary data. The first specific aim involves extensive phenotypic characterization of the decidual T cell population, since further studies are predicated upon this knowledge. Detailed and definitive studies using flow cytometry, immunohistochemistry, quantitative cDNA analysis, and hybridoma production of lymphocytes obtained from reproductive tissues from several points during gestation are proposed. The second specific aim proposes to probe the function of specific subsets of decidual T cells by selective depletion of T cell subsets by mAb injection. Since evidence exists implicating abnormal immune activation in mediating a variety of reproductive complications, specific aim number three. investigates the effect of selective immune activation of various T cell subsets during gestation. Preliminary experiments demonstrate recognition of trophoblasts by a subset of gamma delta cells, and this is the only direct immune recognition of trophoblasts yet demonstrated. As such, this gamma delta cell subset is amongst those chosen for activation. Activation will be achieved by stimulatory doses of injected mAb, or by injection of stimulatory peptide. Preliminary studies indicate profound effects of certain of such manipulations, specifically the depletion of alpha beta T cells during the periimplantation period, and so specific aim number four investigates the mechanism of pregnancy loss in such depleted pregnancies. This will be accomplished by a combined approach using immunohistochemical studies of tissues of depleted mice undergoing pregnancy loss, by double depletion experiments wherein possible effector subsets are codepleted with alpha beta T cell depletions, and by cytokine analysis of supernatants of placental explants of resorbing pregnancies.
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