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반복 유산환자의 말초혈액 단핵구와 태반항원을 체외 공동 배양시 세포 매개 면역반응에 프로게스테론이 미치는 영향
최범채,Choi, Bum-Chae,Hill, Joseph A. 대한생식의학회 1997 Clinical and Experimental Reproductive Medicine Vol.24 No.3
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 Th1-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 Th1-type immunity to trophoblast. IFN-${\gamma}$ was detected in 17 of 23 (74%) trophoblast stimulated PBMC culture supernatants ($77.94{\pm}23.79$ pg/mL) containing embryotoxic activity. TNF-${\alpha}$ was detected in 19 (83%) of these same supernatants ($703.15{\pm}131.36$ pg/mL). In contrast, none of the supernatants contained detectable levels of IL-4 or IL-10. Progesterone ($10^{-5}$, $10^{-7}$, $10^{-9}$M) inhibited Th1-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 Th1-type cytokine secretion but had no effect on Th2-type cytokines. These data suggest that therapies designed to suppress Th1-type cytokine secretion in women with recurrent abortion who have evidence of Th1-type immunity to trophoblast may be efficacious in preventing pregnancy loss and should be tested in appropriately designed clinical trials.
반복유산을 경험한 환자에서 임신중 태반항원과 동종항원에 노출된 모체 림프구면역반응은 언제부터 소실되나?
최범채,Choi, Bum-Chae,Hill, Joseph A. 대한생식의학회 1998 Clinical and Experimental Reproductive Medicine Vol.25 No.2
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 Th1 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 occmed 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.
원인불명 반복 유산환자의 말초혈액 단핵구와 태반항원을 체외 배양 후 생성된 TGF-β1 변화와 프로게스테론의 역할
최범채,Joseph A. Hill 대한산부인과학회 1998 Obstetrics & Gynecology Science Vol.41 No.3
Cross reacting properties of Th1-type and Th2-type cytokines have been proposed to play a role in both murine and human early pregnancy with Th2-type cytokines associated successful pregnancy and Th1-type cytokines with pregnancy loss. TGF-β1 is an important immunoregulatory molecule which can either promote or inhibit Th1-type immunity depending on the susceptibility of T-cells to produce IL-2. The purpose of this study was to determine the ability of peripheral blood mononuclear cells[PBMCs] from women with and without unexplained recurrent abortion[URA] to secrete TGF-β1 following exposure to trophoblast and to determine whether progesterone at levels attained at the maternal-fetal interface[10-5M], affected TGF-β1 secretion in these cultures. PBMCs were isolated from 30 nonpregnant women with URA and from 10 non pregnant fertile controls. Following 4 days of culture [1×106 cells/mL] with and without trophoblast extract[30 ㎍/mL] and with and without progesterone[10-5M]. TGF-β1 was measured by ELISA. Women with URA[median 4, range 2-12] had significantly lower levels of TGF-β1 in unstimulated culture supernatants compared to fertile controls [0.87± 0.08 ng/mL vs. 1.47±0.22 ng/mL; p<0.05]. TGF-β1 levels were not affected by trophoblast or progesterone in women with URA[0.97±0.11 ng/mL vs. 0.95±0.09 ng/mL, respectively]. Incontrast, TGF-β1 levels were significantly decreased in trophoblast stimulated compared to unstimuated PBMC cultures from fertile controls [0.92±0.21 ng/mL vs. 1.47±0.22 ng/mL; p<0.05]. TGF-β1 secretion in fertile women in response to trophoblast was attenuated by progesterone[0.92±0.21ng/mL vs. 1.09±0.20ng/mL, relatively]. These data indicate that there are significant differences in TGF-β1 regulation in reponse to trophoblast and progesterone between women with URA and women with normal reproductive histories.