45 Mouse labyrinthine Dabrafenib clinical trial trophoblasts express paternal MHC class I.46 The interplacentomal trophoblasts of the cow express both classical and non-classical MHC class I genes late in pregnancy.47 As in other species, MHC class II molecules are not expressed by any equine trophoblast populations.36,48

While the pregnant mare is capable of mounting a robust and reproducible humoral immune response against paternal MHC class I antigens, this is not the case with the cell-mediated immune response. Equine pregnancy appears to induce a state of ‘split tolerance’ to trophoblast – a situation where one compartment of the immune system responds to an antigen, while another is tolerant.49–51 In the pregnant mare, this presents as a dramatic allospecific anti-paternal humoral immune response with a simultaneous dampening of certain T-cell-mediated responses. Peripheral blood lymphocytes isolated from pregnant mares demonstrate

a reduced capacity to develop into effective cytotoxic T lymphocytes (CTL) capable of lysing target cells from the breeding stallion.52 This reduction Olaparib nmr in T-cell-mediated alloreactivity reverts after parturition or pregnancy termination, and it is not observed in males or non-pregnant females. This phenomenon seems logical, as the formation of anti-paternal cytotoxic cells during pregnancy could be disastrous for the semi-allogeneic fetus. However, a generalized reduction Guanylate cyclase 2C in cell-mediated immunity would make the mother susceptible to certain types of infections. It has not yet been

determined whether the alteration in the CTL activity of pregnant mares is limited to responses against paternal alloantigens. Studies using transgenic mice have demonstrated that peripheral maternal lymphocytes specific for paternal antigens may be inactivated or deleted during pregnancy.53–55 Studies of infectious diseases in conventional pregnant mice suggest broader antigen-independent mechanisms.56,57 Likewise, pregnant women appear to experience an increased susceptibility to infections such as Listeria and Toxoplasma.58,59 While mares are vulnerable to a number of pregnancy-associated abortogenic infections,60–62 it is not clear whether this is attributable to a general systemic immune tolerance or pregnancy-associated tissue tropism. The peripheral lymphocyte populations of pregnant mares have demonstrated a few significant detectable alterations in phenotype. A modest increase in the number of circulating lymphocytes that express the TH2 cytokine IL-4 has been demonstrated during pregnancy.49 This finding is consistent with the high levels of paternal alloantibodies observed during pregnancy, as the presence of IL-4 favors a humoral immune response. The maternal leukocytes that accumulate around the equine endometrial cups represent one of the most dramatic examples of a local cellular immune response to the conceptus.