No abstract available.
Cell Proliferation* ; Female ; Humans ; Trophoblasts*

The maintenance of a viable pregnancy has long been viewed as an immunological paradox. The deveolping embryo and trophoblast are immunologically foreign to the maternal immune system due to their maternally inherited genes products and tissue-specific differentiation antigens (Hill & Anderson, 1988). Therefore, speculation has arisen that spontaneous abortion may be caused by impaired maternal immune tolerance to the semiallogenic conceptus (Hill, 1990). Loss of recall antigen has been reported in immunosuppressed transplant recipients and is associated with graft survival (Muluk et al., 1991; Schulik et al., 1994). Progesterone (10(-5)M) has immunosuppressive capabilities (Szekeres-Bartho et al., 1985).Previous study showed that fertile women, but not women with unexplained recurrent abortion(URA), lose their immune response to recall antigens when pregnant (Bermas & Hill, 1997). Therefore, we hypothesized that immunosuppressive doses of progesterone may affect proliferative response of lymphocytes to trophoblast antigen and alloantigen. Proliferative responses using 3H-thymidine (3H-TdR) incorporation of peripheral blood mononuclear cells (PBMCs) to the irradiated allogeneic periperal blood mononuclear cells as alloantigen, trophoblast extract and Flu as recall antigen, and PHA as mitogen were serially checked in 9 women who had experienced unexplained recurrent miscarriage, Progesterone vaginal suppositories (100mg b.i.d; Utrogestan, Organon) beginning 3 days after ovulation were given to 9 women with unexplained RSA who had prior evidence of Thl immunity to trophoblast. We checked proliferation responses to conception cycle before and after progesterone supplementation once a week through the first 7 weeks of pregnancy All patients of alloantigen and PHA had a positive proliferation response that occured in the baseline phase. But 4 out of 9 patients (44.4%) of trophoblast antigen and Flu antigen had a positive proliferative response. The suppression of proliferation response to each antigen were started after proliferative phase and during pregnancy cycles. Our data demonstrated that since in vivo progesterone treated PBMCs suppressed more T-lymphocyte activation and 3H-TdR incorporation compare to PBMCs, which are not influenced by progesterone. This data suggested that it might be influenced by immunosuppressive effect of progesterone. In conclusion, progesterone may play an important immunological role in regulating local immune response in the fetal-placental unit. Furthermore, in the 9 women given progesterone during a conception cycle, Only two (22%) repeat pregnancy losses occured in these 9 women despite loss of antigen responsiveness (one chemical pregnancy loss and one loss at 8 weeks of growth which was karyotyped as a Trisomy 4). These finding suggested that pregnancy loss due to fetal aneuploidy is not associated with immunological phenomena.
Abortion, Habitual ; Abortion, Spontaneous* ; Aneuploidy ; Antigens, Differentiation ; Embryonic Structures ; Female ; Fertilization ; Graft Survival ; Humans ; Immune System ; Immune Tolerance ; Isoantigens* ; Lymphocytes* ; Ovulation ; Pregnancy ; Progesterone ; Suppositories ; T-Lymphocytes ; Transplantation ; Trisomy ; Trophoblasts*

Progesterone is necessary for successful pregnancy and had immunosuppressive properties. Peripheral blood mononuclear cells (PBMC) from many women with unexplained recurrent spontaneous abortion responded to trophoblast extract in vitro by prolifertion and releasing soluble, heat-labile factors that are toxic to mouse embryos (embryotoxic factors). Accumulating evidence suggests that T Helper (Th)-1 type immunity to trophoblast is correlated with embryotoxic factor production and is associated with pregnancy loss, while Th2-type immunity is associated with successful gestation. The objective of this study was to determine whether progesterone can inhibit Thl-type cytokine secretion (IFN-gamma, TNF-alpha) by trophoblast-activated peripheral blood mononuclear cells from 23 nonpregnant women (age 25-35) with unexplained recurrent abortion (median 5, range 3 to 15)who otherwise produce embryotoxic factors in response to trophoblast. We also determined whether progesterone affected Th2-type cytokines (IL-4, IL-10) in this system in vitro and if IL-10 (1,500 pg/mL) could inhibit Thl-type immunity to trophoblast. IFN-gamma was detected in 17 of 23 (74%) trophoblast stimulated PBMC culture supernatants (77.94+/-23.79 pg/mL) containing embryotoxic activity. TNF-alpha was detected in 19 (83%) of these same supernatants (703.15+/-131.36 pg/mL). In contrast, none of the supernatants contained detectable levels of IL-4 or IL-10. Progesterone (10-5, 10-7, 10-9M) inhibited Thl-type immunity in a dose dependent manner, but had no effect on Th2-type cytokine secretion. The inhibitory effects of progesterone were abrogated with RU486, but did not affect Th2-type cytokine secretion in trophoblast-activated cell cultures. IL-10, like progesterone also inhibited Thl-type cytokine secretion but had no effect on Th2-type cytokines. These data suggest that therapies designed to suppress Thl-type cytokine secretion in women with recurrent abortion who have evidence of Thl-type immunity to trophoblast may be efficacious in preventing pregnancy loss and should be tested in appropriately designed clinical trials.
Abortion, Habitual ; Abortion, Spontaneous ; Animals ; Cell Culture Techniques ; Cytokines ; Embryonic Structures ; Female ; Humans ; Immunity, Cellular* ; Interleukin-10 ; Interleukin-4 ; Mice ; Mifepristone ; Pregnancy* ; Progesterone* ; Trophoblasts* ; Tumor Necrosis Factor-alpha