In vitro, peripheral equine NK-like lymphokine activate Pifithrin-�� in vitro killing cells have
shown the capacity to lyse differentiated MHC class I negative binucleate chorionic girdle cells.111 However, their role in vivo has not been determined. Studies of porcine pregnancy have demonstrated that NK cells can be recruited to the uterus of a species with epitheliochorial placentation.112 The advent of new reagents to detect equine NK cells should help address this question. A second pressing question is why and how the endometrial cups are ultimately destroyed after 2 months of successful evasion of maternal immune effectors. Clusters of CD4+ and CD8+ lymphocytes and inflammatory leukocytes are seen within sections of dying cups.63 Here, in the absence of MHC class I antigen expression, it is possible that NK cells could be acting as cytotoxic cells. However, it is not clear
whether infiltrating immune cells are a primary cause of destruction of the cups or if they simply undergo apoptosis at the end of their natural lifespan. Evidence for an immunological basis for endometrial cup destruction has been demonstrated by experimental interspecies matings. In a standard MHC-incompatible horse mating, there is no change in the lifespan of the cups with multiple pregnancies.42 However, when mares are mated to male donkeys to produce mule pregnancies, the cups are destroyed earlier in subsequent pregnancies, suggestive
of an anamnestic R788 order response.113 Lymphocytes from mares carrying mule pregnancies do not demonstrate reduced CTL activity in vitro against cells from the donkey sire,52 indicating a failure in the systemic dampening of cell-mediated immunity in these interspecies matings. A more dramatic version of an apparent immune-based destruction of the endometrial cups is seen in the donkey-in-horse pregnancy model. While most females of the genus Equus can successfully carry a pregnancy from any of the other species following embryo transfer, 3-oxoacyl-(acyl-carrier-protein) reductase only rarely can a horse maintain a transferred donkey embryo.114,115 In this situation, the chorionic girdle fails to invade the endometrium of the surrogate mare. No endometrial cups form, and there is no detectable eCG in the serum. Large numbers of endometrial leukocytes are seen at the border of the non-invasive allantochorion, which abnormally expresses MHC class I antigens and fails to interdigitate with the maternal endometrium.37,116,117 Furthermore, these mares carrying embryo transfer donkey conceptuses also appear to demonstrate an anamnestic response; mares that abort one donkey pregnancy abort subsequent pregnancies of this type earlier in gestation.117 The breeding of in utero immunotolerized chimeric twins has also lent insights into the role of immune mechanisms in endometrial cup destruction.