Cyclosporin A improves murine pregnancy outcome in abortion-prone matings: involvement of CD80/86 and CD28/CTLA-4

Abstract

Immune regulation during pregnancy is complex, and thus an optimal therapy for pregnancy complications is always a big challenge to reproductive medicine. Cyclosporin A (CsA), a potent immunosuppressant, prevents rejection of allografts by hosts, but little is known about the modulating effect of CsA on the materno-fetal relationship. Here, pregnant CBA/J females mated with DBA/2 males as an abortion-prone model were administered with CsA on day 4.5 of gestation, and the pregnant CBA/J females mated with BALB/c males were established as successful pregnancy control. It was demonstrated that administration of CsA at the window of implantation significantly up-regulated the expression of CTLA-4, while down-regulating the levels of CD80, CD86, and CD28 at the materno-fetal interface in the CBA/J!DBA/2 abortion-prone matings, and the embryo resorption rate of the abortion-prone matings reduced significantly after CsA treatment, implying that modulation of costimulatory molecule expression by CsA might contribute to preventing the fetus from maternal immune attack. In addition, treatment with CsA induced enhanced growth and reduced cell apoptosis of the murine trophoblast cells. Together, these findings indicate that CsA has a beneficial effect on the materno-fetal interface in abortion-prone matings, leading to a pregnancy outcome improvement, which might provide new therapeutics for spontaneous pregnancy wastage. Reproduction (2008) 135 385-395

REVIEW ARTICLE: Regulatory T Cells and Their Role in Pregnancy

“…72 Importantly, CsA injection further reduced the abortion rate of abortion-prone females significantly. 72 Miranda and colleagues 73 further showed that syngeneic DC administration into DBA ⁄ 2J-mated CBA ⁄ J females diminished the abortion rate that was associated with an increase in the number of CD8 and cd cells. Additionally, they observed an up-regulation of TGF-b1 and progesterone induced blocking factor expression.…”

“…71 The administration of Cyclosporin A (CsA) on day 4.5 of gestation into abortion-prone mice significantly up-regulates the Treg-associated molecule CTLA-4, while down-regulating the levels of costimulatory molecules such as CD80, CD86, and CD28 at the fetal-maternal interface. 72 In addition, treatment with CsA induced enhanced growth and reduced cell apoptosis of murine trophoblasts. 72 Importantly, CsA injection further reduced the abortion rate of abortion-prone females significantly.…”

“…72 In addition, treatment with CsA induced enhanced growth and reduced cell apoptosis of murine trophoblasts. 72 Importantly, CsA injection further reduced the abortion rate of abortion-prone females significantly. 72 Miranda and colleagues 73 further showed that syngeneic DC administration into DBA ⁄ 2J-mated CBA ⁄ J females diminished the abortion rate that was associated with an increase in the number of CD8 and cd cells.…”

“…69 Other groups also employed this model to confirm the protective role of Treg during pregnancy. [71][72][73] The injection of anti-B7-1 and anti-B7-2 mAbs to 4-days pregnant CBA ⁄ J females favors the generation of T cells having a regulatory phenotype. 71 Anti-B7 treated 'regulatory' T cells that were subsequently transferred into abortion-prone females were able to overcome increased fetal rejection.…”

The Galectin-9/Tim-3 pathway is involved in the regulation of NK cell function at the maternal–fetal interface in early pregnancy

“…For example, T helper (Th)2 cytokine polarization, 4 the expression of non-classical major histocompatibility complex molecules on trophoblast cells, 5,6 the inhibition of complement activation, 7,8 and a delicate balance between costimulatory (CD80 and CD86) and co-inhibitory (CTLA-4 and PD-1) signals have been observed in normal pregnancies. 9 In addition, immunoregulatory molecules, including indoleamine 2,3-dioxygenase, interleukin (IL)-10 and transforming growth factor-b, are expressed at high levels at the maternal-fetal interface. 10,11 Decidual natural killer (dNK) cells, the dominant lymphocyte population that accumulates in the decidua, play a pivotal role in successful pregnancies.…”