Th1 and Th2 cytokine profiles in recurrent aborters with successful pregnancy and with subsequent abortions

Human Reproduction Th1 and Th2 cytokine profiles in recurrent aborters with successful pregnancy and with subsequent abortions M.Makhseed 1 3 R.Raghupathy 1 2 F.Azizieh 1 2 A.Omu 1 3 E.Al-Shamali 0 1 L.Ashkanani 0 1 0 Maternity Hospital , Kuwait 1 P. O.Box 24923, Kuwait 13110 2 Microbiology, Faculty of Medicine , Kuwait University 3 Obstetrics & Gynecology BACKGROUND: This study compared Th1-Th2 cytokine profiles in a subgroup of recurrent aborters who had an abortion with those in a subgroup of recurrent aborters who had a successful pregnancy. METHODS: Fiftyfour women with a history of at least three normal pregnancies, 24 women with a history of recurrent spontaneous abortion (RSA) followed by abortion (RSAA) and 39 women with a history of RSA followed by normal pregnancy (RSAN) were studied. Blood samples and placentas were obtained at the time of delivery or abortion; peripheral blood mononuclear cells were stimulated separately with phytohaemagglutinin and with autologous placental cells, and the secreted cytokines estimated. RESULTS: Peripheral blood mononuclear cells from the RSAN subgroup secreted higher concentrations of Th1-type cytokines as compared with normal pregnant women, indicating a higher Th1 bias in these women. However, women in the RSAN subgroup had significantly higher concentrations of Th2 cytokines as compared with women in the RSAA subgroup. A comparison of Th1:Th2 cytokine ratios indicated a higher Th2 bias in RSAN women as compared with RSAA women. CONCLUSIONS: We conclude that abortion-prone women who proceed to have successful pregnancy are more Th2-biased than abortion-prone women who abort, and that recurrent aborters who undergo spontaneous abortion have a stronger Th1 bias than aborters who have normal pregnancy. pregnancy/recurrent spontaneous abortion/Th1 cytokines/Th2 cytokines - Cellular immune effector mechanisms have been proposed as being responsible for at least a proportion of unexplained recurrent spontaneous abortions (RSA) (Hill, 1995; Raghupathy, 1997). Unexplained RSA accounts for about 4060% of all cases of RSA (Stray-Pederson and StrayPederson, 1984). Recent evidence, much of it emerging from research on animal models, indicates important roles for T cells, macrophages, natural killer (NK) cells and cytokines in causing pregnancy failure (Wegmann et al., 1993; Hill, 1995; Chaouat and Menu, 1997; Raghupathy, 1997; Clark, 1999; Clark et al., 1999). Clark and colleagues have proposed that an abortogenic pathway consisting of macrophages, NK cells and T cells and the cytokines tumour necrosis factor (TNF), interferon (IFN)- and interleukin (IL)-2 may underlie immunologically mediated abortions (Clark et al., 1998). Resorption sites in mice are infiltrated by NK cells (Gendron and Baines, 1988) and activated macrophages (Baines et al., 1997). The administration of the cytokines TNF-, IFN- or IL-2 to normal pregnant mice causes abortions (Chaouat et al., 1990; Tezabvala et al., 1989). TNF- stimulates the programmed death of human primary villous trophoblast cells, and IFN- augments TNF-mediated killing of trophoblasts (Yui et al., 1994). IL-2, IFN- and TNF-, i.e. cytokines that have deleterious effects on the conceptus, are cytokines that are characteristic of so-called Th1-type cells, which induce several cytotoxic and inflammatory reactions and are thus responsible for the induction of cell-mediated inflammatory reactions (Mosmann and Coffman, 1989; Romagnani, 1994; Mosmann and Sad, 1996). Th2 cells, on the other hand, secrete IL-4, IL-5, IL-6, IL-10 and IL-13 and are associated with help for humoral immunity. Based on the observations of deleterious effects of Th1-type cytokines on murine pregnancy and on observations that pregnancy appears to be associated with a down-regulation of cell-mediated immunity manifested as reduced delayed-type hypersensitivity (DTH) (Holland et al., 1984), NK activity (Luft and Remington, 1984) and weakened resistance to intracellular infections (Wegmann et al., 1993), it was suggested that pregnancy is associated with a down-regulation of Th1-type activity and enhancement of Th2-type activity (Wegmann et al., 1993; Hill, 1995; Raghupathy, 1997). In humans, elevated concentrations of the Th1-type cytokines IL-2 and IFN-, and decreased concentrations of the Th2-type cytokine IL-10, have been reported in spontaneous abortion upon antigen- and mitogen-induced activation of maternal peripheral blood mononuclear cells (PBMC) (Marzi et al., 1996). The activation of PBMC with trophoblast antigens followed by cytokine analyses has shown that women with unexplained RSA have a Th1-type profile (Hill et al., 1995). We have recently demonstrated increased production of IFN-, TNF-, TNF- and IL-2 by mitogen-activated PBMC from women with RSA and, conversely, increased production of IL-4, IL-5, IL-6 and IL-10 by PBMC from women with normal pregnancy at the end of the first trimester (Raghupathy et al., 2000) and at delivery (Makhseed et al., 1999). We have shown a similar Th1 bias in unexplained RSA and a Th2 bias in successful pregnancy by comparing cytokine production after stimulation with autologous placental cells and with trophoblast antigens (Raghupathy et al., 1999). A recent study showed significantly higher concentrations of IL-4- and IL-10producing T cell clones generated from cells infiltrating the decidua of women with normal pregnancy as compared with those experiencing unexplained RSA (Piccinni et al., 1998). Indeed, it has been demonstrated (Ekerfelt et al., 1997) that there is a significantly larger number of IL-4-secreting maternal cells in response to stimulation with paternal leukocytes as compared with other, unrelated leukocytes, suggesting a selective and specific immune deviation towards Th2 bias in normal pregnancy. Taken together, these data provide significant support for the contention that women with normal pregnancy have a higher Th2 bias, whereas women with a history of unexplained RSA have a bias towards Th1-type reactivity. This communication focuses on a subgroup of women who have a history of recurrent abortions but go on to have a successful pregnancy. We felt it to be of great interest to determine the Th1Th2 cytokine profiles in this group of women and to compare these profiles with those in recurrent aborters who have another spontaneous abortion. The objective of this study was to compare the cytokine profiles in abortionprone women who had a successful pregnancy (RSAN) with abortion-prone women who had a spontaneous abortion (RSAA) and with women who have had a history of at least three successful pregnancies and no previous abortions (N). Cultures of maternal PBMC obtained at the time of abortion or delivery were stimulated with the mitogen phytohaemagglutinin (PHA) and with autologous placental cells, after which cytokine concentrations were estimated. Materials and methods Subjects were selected at the Kuwait Maternity Hospital from patients with three (...truncated)