68 indoleamine 2, 3-dioxygenase (IDO), which is expressed by trophoblasts, also induces profound T-cell anergy. Indeed, neutralisation of IDO induces abortion solely in allopregnancies with rates

varying with the mating combination.69 IDO KO mice breed, which is often presented AZD1208 order as a negative argument, but these are synpregnancies not allopregnancies. The physiological situation for this requires IDO KO in two different strains. Two mechanisms can explain clonal deletion. First, Fas/Fas ligand interaction: outer trophoblasts express Fas ligand with a weaker expression at term. Activated T cells express Fas, and the interaction of Fas with FasL induces death by apoptosis. Thus, any anti-paternal alloantigen T cells are immediately destroyed when binding trophoblasts.70 Such T cell encounters in the periphery (bone marrow) with deported trophoblasts would explain micro-chimerism. However, allopregnancies are normal in double Fas/FasL matings.71 Another mechanism with similar consequences is the secretion of sHLA-G, which kills activated

T cells.72 Clonal deletion becomes, as a consequence, deeper, as pregnancy progresses, and reverts in absence of a placenta. The Th1/Th2 paradigm73 supposes a shift to Th2 predominance during pregnancy, which at the foetal–placental interface would create a transient hypo-responsive (privileged) site. Indeed, the main HM781-36B cost Th2 cytokine, IL-10, is present at both sides of the foetal–placental interface,59,74 and IL-10 prevents resorptions in CBA × DBA/2 matings.75 However, IL-10 KO mice or deletion of 4 Th2 by KO simultaneously in one mouse76 does not affect foetal health. But Sharma and Robertson have shown data that while IL-10 KO mice develop normally, they are more susceptible to LPS-induced abortion,77,78 somehow linking IL-10 with ‘danger’. Loperamide Finally, three more mechanisms should be mentioned, mostly on the ‘uterine side’: TGF-beta produced locally by null cells;79 progesterone-induced blocking factor (PIBF);80 and suppressor/regulatory T cells (Ts/Tregs). TGFs, which are also strong

immunosuppressants, are the sole growth factors being also immunosuppressive. A deficiency of a DLN suppressor factor was first noted in the CBA × DBA/2 mating. The factor proved to be a TGFβ2 analogue.79 TGF-beta has important immunodeviating capacities during implantation. Trophoblast MHC class I recognition elicits progesterone receptor (PgR) expression on hitherto PgR-lymphocytes, which in the presence of high doses of progesterone, seen only at the placental–foetal interface, induces PIBF secretion itself.80 All of these mechanisms are redundant, and the soluble factors act at high doses, thus only locally, creating a quasi-immunologically privileged site without affecting systemic immunity.