Progesterone-mediated immunomodulation in pregnancy: its relevance to leukocyte immunotherapy of recurrent miscarriage

Abstract

Progesterone is crucial for the establishment and maintenance of pregnancy. Progesterone-regulated genes in the pregnant uterus control the development of endometrial receptivity as well as recruitment and differentiation of decidual NK cells, which in turn act on angiogenesis and trophoblast invasion. The link between progesterone and the immune system is established by lymphocyte progesterone receptors expressed in peripheral blood γδ T cells of pregnant women and in peripheral NK cells. Regulation of lymphocyte progesterone receptors is activation related, thus efficient recognition of fetal antigens is a requirement for the initiation of progesterone-dependent immunoregulatory mechanisms. Several immunological effects of progesterone are mediated by progesterone-induced blocking factor – the product of a progesterone-induced gene in lymphocytes. One part of unexplained recurrent miscarriages might have an immunological etiology. Immunization of the mothers with paternal or third-party leukocytes aims to correct the misregulated antifetal immune response. There are, however, serious concerns about this treatment, including the lack of information about the mode of action and possible adverse effects of the treatment, the failure to detect a significant effect of immunotherapy and the lack of a reliable generally accepted marker for patient selection. These concerns will be discussed in this review.