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Context: Implantation of fertilised eggs and survival of a semi-allogenic embryo rely on the interactions between the cells and molecules preparing the uterus. We investigated the effect of regulatory T cell (Treg) therapy on the mechanism of local immune tolerance of mice prone to spontaneous abortion. Methods: Naive T cells were stimulated in vitro with 17β-oestradiol (E2), progesterone (P4) and TGF-β1 for 96 h to generate induced Tregs (iTreg). The iTregs were injected into DBA/2-mated pregnant CBA/J female mice (abortion prone model). On day 14 of pregnancy, mice were killed and decidual and placental tissues were collected for cellular composition analysis. Results: Abortion prone mice (PBS treated) showed significantly lower survival rates (P < 0.0001), increased CD3+CD8+ (P < 0.05), lower IDO+ (P < 0.05) and increased natural killer cells (uNK) cell numbers (P < 0.001) in the uterus, as well increased NK cells in the placenta (P < 0.05) than in normal pregnant mice (CBA/J × BALB/c). Adoptive transfer of iTregs increased fetal survival in abortion-prone mice (P < 0.01) and histopathological evaluation revealed a significantly decreased number of uNK cells in the uterus of TGF-β1-, E2- and P4-iTregs (P < 0.05, P < 0.0001 and P < 0.05, respectively) than in the PBS treated group. In the placenta, we found significantly lower numbers of uNK cells from TGF-β1-, E2- and P4-iTregs than in the PBS treated group (P < 0.05, P < 0.05 and P < 0.01, respectively). Conclusions: We propose that modulation of uterine NK cell activity through immunotherapy using Treg cells should be given more attention as an immunological strategy in the treatment of recurrent miscarriage. Recurrent spontaneous abortion has been associated to imbalanced cellular immunological status. Adoptive transfer of induced regulatory T cells promoted survival rate and corrected dysregulated uterine natural killer cells. Induced regulatory T cells might have potential therapeutic benefits in women with recurrent spontaneous abortion. [ABSTRACT FROM AUTHOR]

Ovarian hormones drive in vivo generation of regulatory T cells (Tregs) during pregnancy. Little is known about the therapeutic potential of in vitro hormone-derived Tregs in pregnancy loss. We investigated the effects of hormone-induced Tregs in a murine model of abortion. CD4+CD25– T cells were isolated from the spleens of CBA/J mice and stimulated with either 17β-oestradiol (E2), progesterone (P4) or transforming growth factor-β1 (TGFB1) plus retinoic acid (RA) for 4 days to generate induced Tregs (iTregs). On Days 1–4 of gestation, DBA/2-mated pregnant CBA/J female mice (abortion prone) were injected intravenously with iTregs or Tregs isolated from normal BALB/c-mated pregnant CBA/J mice (np-Tregs). On Day 14, the number of resorbed fetuses was assessed. Serum interferon (IFN)-γ and uterine forkhead box p3 (Foxp3) expression was analysed by ELISA and immunohistochemistry respectively. Using a 3H-thymidine incorporation assay, isolated CD4+CD25+ Tregs induced by the different treatments suppressed the proliferation of CD4+CD25– T cells. Adoptive transfer of iTregs (from all induction groups) significantly decreased fetal resorption in abortion-prone mice. There were no significant changes in serum IFN-γ concentrations after the adoptive transfer of iTregs or np-Tregs. Immunohistochemistry revealed significantly higher Foxp3 expression in gravid uteri from mice injected with np-Tregs and P4-induced iTregs than in the phosphate-buffered saline-treated group. The findings of this study indicate a potential therapeutic benefit of in vitro -induced Tregs in patients with recurrent abortion. Recurrent spontaneous abortion (RSA) has been associated with a deficiency in maternal regulatory T cells (Tregs). Adoptive transfer of Tregs may play a role in protecting embryos in women with RSA. Adoptive transfer of induced (i) Tregs resulted in normal pregnancy rates in abortion-prone mice. iTregs may have potential therapeutic benefits in patients with RSA. [ABSTRACT FROM AUTHOR]

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