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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.
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.
습관성 유산 환자 혈청에서 종양 괴사인자 - 알파 측정
최범채(BC Choi),유근재(KJ Yoo),이종표(JP Lee),백은찬(EC Baik),조동희(DH Cho),강인수(IS Kang) 대한산부인과학회 1998 Obstetrics & Gynecology Science Vol.41 No.1
Pregnancy must be considered as a successful allotransplant and certain forms of recurrent spontaneous abortions(RSA) are probably due to transplant rejection. Tumor necrosis factor-alpha(TNF-α)may play a key role in the rejection of transplants as elevated TNF-α serum levels have been found in organ transplantation patients during acute rejection crisis(Herrmann and Mertelsmann 1989). In this study, we measured the serum levels of TNF-α to elucidate the relationship between TNF-α and RSA, and to evaluate the value of TNF-α as a new prognostic marker in RSA. Sixty-seven women visited to Samsung Cheil Hospital from November, 1994 to August, 1995 of whom 15 were diagnosed as healthy and nonpregnant(Group A), 29 were dignosed as having RSA(Group B), 15 were diagnosed as pregnant with no complications(Group C), and 8 were of diagnosed as having an abortion between the 6th and 12th week of pregnancy(Group D). The blood levels of TNF-α were measured by use of QuantikineTM HS Immunoassay kit with a sensitivity of 0.125 pg/mL for the benchtop assay(R&D systems). The average serum level(Mean ± SEM) of TNF-α in Group A, B, C and D were 1.89 ± 0.18 pg/ml, 2.95 ± 0.46 pg/mL, 2.42 ± 0.26 pg/mL, and 3.55 ± 1.31 pg/mL, respectively. The level of TNF-α in pregnant women was relatively higher than that of non-pregnant women, however, no stastically significant differences were observed between these two groups. In the total study population, neither age nor number of prior pregnancy losses significantly correlated with TNF-α serum levels. There was no difference between women who had abortions caused by known etiology and those who successfully carried to 28 weeks(2.450.68 pg/ml versus 2.420 ± 6 pg/mL). However, women who had abortions caused by unknown etiology showed an increase in serum TNF-α compared to women with normal pregnancies(4.65 ± 2.59 pg/mL versus 2.42 ± 0.26 pg/mL, relatively). Similarly, women with a history of unexplained recurrent abortion were more likely to secrete TNF-α than healthy, nonpregnant women(4.11 ± 0.93 pg/mL versus 1.89 ± 0.18 pg/mL, p < 0.05). These data suggest that unexplained recurrent abortion might be correlated with increased serum TNF-α levels.
최범채(BC Choi),김수녕(SN Kim),조인제(IJ Cho),김두호(DH Kim) 대한산부인과학회 1993 Obstetrics & Gynecology Science Vol.36 No.3
Primary ovarian pregnancy is a rare form of ectopic pregnancy, with an estimated overall incidence of 1 in 7,000 pregnancies. Ovarian pregnancy occurs within the ovary and on the corpus luteum, usually with rupture of the ovary and a massive hemoperitoneum. It presents as a hemorrhagic ovary and is frequently misdiagnosed as a ruptured corpus luteum. We have experienced two cases of ovarian pregnancy and report with brief review of literatures.