The long range goal of this project is to better understand the fetal-maternal immunologic balance during pregnancy. In particular, the possible regulatory effects of natural killer (NK) cells on the developing fetus and trophoblast as well as the effects of pregnancy hormones on NK cells will be explored. The central hypothesis to be tested is that the unique endocrine and cytokine milieu of pregnancy stimulates the proliferation and maturation of NK lineage cells into differentiated secretory cells that play a central role in the regulation of mammalian pregnancy. This hypothesis will be tested in mice in terms of 3 specific questions. 1) Are NK cells required for a normal, successful pregnancy? Female B6 mice chronically depleted of NK cells with NK 1.1 MAb will be used to detect effects on implantation and the subsequent growth of the fetal-placental unit. 2) Does pregnancy affect the differentiation of bone-marrow derived NK lineage cells? Limiting dilution assays will be used to estimate the frequency of NK precursors in bone marrow from pregnant mice. IL-2 titers in pregnant mice will be measured and the effects of estradiol-17 beta and progesterone on NK cell response to IL-2 will be assessed in vitro. 3) Do differentiated NK lineage cells secrete factors which are tophic or inhibitory for the trophoblast and/or fetus? A population of large granulated cells in the decidua of mice (granulated metrial gland - GMG - cells) has been suggested to be NK-like. 4H12+ GMG cells from the decidua and spleen cell-derived A-LAK cells will be probed by in situ hybridization for mRNA transcripts for TNF-alpha, IFN-gamma, GM-CSF and CSF-1 and tested for secretion of those factors. Finally, the effects of 4H12+ GMG and A-LAK cells will tested on cultured trophoblast cells. These studies could have direct relevance for understanding recurrent spontaneous abortion as well as the normal control mechanisms of pregnancy. This work may also expand an understanding of the activities of IL-2 activated NK cells and thus relate to tumor immunology.
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