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Cyclosporin A Improves Pregnancy Outcome by Promoting Functions of Trophoblasts and Inducing Maternal Tolerance to the Allogeneic Fetus in Abortion-Prone Matings in the Mouse¹

Laboratory for Reproductive Immunology,³ Hospital and Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai 200011, China Department of Obstetrics & Gynecology,⁴ The Affiliated Hospital, Hainan Medical College, Haikou 570102, China

ABSTRACT

The embryo expresses paternal antigens foreign to the mother, and therefore has been viewed as a natural allograft. Cyclosporin A (CsA) is an immunosuppressant for preventing allograft rejection. Little is known, however, about the modulating effect of CsA on the materno-fetal relationship. In this study, pregnant CBA/J female mice mated with DBA/2 or BALB/c male mice as abortion-prone and normal pregnancy matings were administered, respectively, with CsA at Day 4 of gestation. We demonstrated that the administration of CsA at the window of implantation resulted in maternal T-cell tolerance to paternal antigen, and it improved pregnancy outcome in the CBA/J DBA/2 abortion-prone matings. CsA administration enhanced Th2 and reduced Th1 cytokine production at the materno-fetal interface, and it expanded peripheral CD4⁺CD25⁺ FOXP3⁺ regulatory T cells in abortion-prone matings, implying development of Th2 bias and regulatory T cells. On the other hand, we observed that treatment with CsA led to enhanced growth and invasiveness of trophoblasts in the abortion-prone matings. Together, these findings indicate that CsA in lower dosages can induce materno-fetal tolerance and improve the biologic functions of trophoblast cells in the abortion-prone matings, leading to a successful pregnancy, which is useful in clinical therapeutics for spontaneous pregnancy wastage and other pregnancy complications.

cytokines,, immunology, placenta, pregnancy, trophoblast

¹Supported by National Key Research Program of China 2006CB0F1009 to D.J.L.; Shanghai Foundations for Basic Research no. 03JC14016 to D.J.L. and no. 06ZR14120 to M.R.D.; Program for Outstanding Medical Academic Leader to D.J.L.; and 985 Foundations of Fudan University no. 985B36 to D.J.L. The authors have no conflict of interest or financial interests.

Correspondence: ²FAX: 0086 21 6345 0768; e-mail: djli{at}shmu.edu.cn

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