This proposal would test the hypothesis that uterine lymphocyte population have an immunoregulatory role in maintaining pregnancy. It would also test an extension of that hypothesis which maintains that such lymphocytes can, in some instances contribute to early abortion. These propositions are in accord with morphological observations and circumstantial evidence based on immunological data a d the results of breeding experiments in several species. However, compelling evidence has been hard to obtain because of the difficulty in recovering uterine lymphocytes in sufficient numbers and in functionally active condition to allow critical in vitro experimentation. Lymphocytes are relatively few in number and are diffusely distributed in the pregnant uteri of most mammalian species, including humans, rats and mice, the principal species studied so far, but not in horses. The situation in equids is unique to the extent that maternal lymphocytes surround and invade the trophoblast cells which comprise anatomically discrete structures, the endometrial cups. We would exploit that species-specific difference to characterize uterine lymphocytes both antigenically and analysis would be undertaken which uses a second unique feature of the equine model, namely, the ability of horses and donkeys to cross-hybridize to produce interspecies mule and hinny pregnancies in which the genetic differences between mother and fetus are increased relative to intraspecies pregnancies. The proposed research would also encompass a study of early fetal death: the abortion between days 80-95 of gestation of donkey conceptuses established in horse mares by embryo transfer. This pregnancy loss is initiated by a non-genetic defect in placental development and has a pathogenesis which appears to have important immunological components. The maternal lymphocytes which comprise the cellular response to the fetal trophoblast in equine endometrial cups in intraspecies horse pregnancy would be characterized with respect to their antigenic phenotype and function and compared with lymphocyte populations in interspecies mule pregnancy as well as those which accumulate and appear to attack the entire trophoblast in failing donkey-in-horse pregnancies. Monoclonal antibodies which we have prepared for this proposed, as well as others that we plan to generate, would be used in these investigations.
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