Defective production of both leukemia inhibitory factor and type 2 T- helper cytokines by decidual T cells in unexplained recurrent abortions

Institute of Internal Medicine and Immunoallergology, University of Florence, Italy.
Nature Medicine (Impact Factor: 28.05). 10/1998; 4(9):1020-4. DOI: 10.1038/2006
Source: PubMed

ABSTRACT Leukemia inhibitory factor is essential for embryo implantation, and a shift from type 1 T-helper to type 2 T-helper response at the fetal-maternal interface may contribute to successful pregnancy. We show that LIF production is associated with type 2 T-helper cells, is upregulated by IL-4 and progesterone and is downregulated by IL-12, IFN-gamma and IFN-alpha. We also show a decreased production of LIF, IL-4 and IL-10 by decidual T cells of women with unexplained recurrent abortions in comparison with that of women with normal gestation. The defective production of LIF and/or type 2 T-helper cytokines may contribute to the development of unexplained recurrent abortions.

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Available from: Marie-Pierre Piccinni, Apr 21, 2015
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    • "Evidence suggests that the mean of the Th1:Th2 ratio in patients with RPL and in patients with multiple implantation failure after IVF-embryo transfer [188] is significantly higher than in normal fertile women. This predominance of Th1 cytokines was demonstrated to exist in endometrial cells as well as peripheral blood mononuclear cells before pregnancy [187] [189] [190] and at the time of miscarriage in decidual cells [191]. However, there are significant discrepancies in the results of the different studies, as some suggest that Th1 cytokines production was higher in normal women than in RPL patients in early pregnancy [192], and others even found that the production of Th1 and Th2 cytokines was similar in RPL patients who subsequently had successful or failed pregnancies [193]. "
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    ABSTRACT: Embryo implantation depends on both embryo quality and the endometrial environment. Implantation failure has a complex, variable pathophysiology and is detrimental to the outcome of in vitro fertilization (IVF). Thus, patients with multiple implantation failure require an individualized approach to diagnosing and managing treatment options for future IVF cycles. These options should be based on concrete, unambiguous, consistent scientific evidence with random-ized, controlled trials. We review and discuss 14 treatment options: (i) blastocyst transfer, (ii) assisted hatching, (iii) co-culture, (iv) preimplanta-tion genetic screening, (v) hysteroscopy, (vi) sildenafil, (vii) salpingectomy for tubal disease, (viii) oocyte donation, (ix) transfer of six or more embryos, (x), intratubal embryo transfer, (xi) natural cycle IVF, (xii) antiphospholipid antibodies (APA) testing and treatment, (xiii) allogenic lymphocyte therapy, and (xiv) IV immunoglobin therapy. The approaches were evaluated based on available information from studies, expert opinions, consensus, etc. We conclude that blastocyst transfer, assisted hatching, salpingectomy for tubal disease, and hysteroscopy in IVF procedures are clinically effective. This review serves as a summary of current treatment options for clinicians to counsel patients and manage their expectations based on strong and reliable evidence.
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    • "Although increased Th1 and Th17 responses in women with recurrent pregnancy loss have been observed, paternal PBMC have, to our knowledge, not been used as a stimulus to examine the maternal immune responses toward fetal antigens before. Strong mitogenic stimuli such as PMA/ionomycin (Piccinni et al., 1998; Kwak-Kim et al., 2003; Sacks et al., 2003; Kalu et al., 2008) or PHA (Makhseed et al., 2001), as well as trophoblast cell line extracts (Raghupathy et al., 1999; Ginsburg et al., 2005) have previously been used as stimuli, whereas we here wanted to investigate paternal antigen-induced responses during in vitro fertilization (IVF) treatment. "
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    ABSTRACT: We aimed to prospectively investigate the paternal antigen-induced cytokine secretion by peripheral blood mononuclear cells (PBMCs) in response to hormone treatment in women undergoing in vitro fertilisation (IVF) and to examine the predictive value of the cytokine secretion profile in the outcome of IVF treatment, in a pilot study. Twenty-five women were included and IVF treatment was successful for six and unsuccessful for 19 women. Blood samples were collected before IVF treatment, on four occasions during IVF and four weeks after embryo transfer. The numbers of Th1-, Th2- and Th17-associated cytokine-secreting cells and cytokine levels in cell supernatants were analysed by enzyme-linked immunospot-forming (ELISpot), enzyme-linked immune-sorbent (ELISA) or Luminex assay. None of the cytokines (IFN-γ, IL-4, IL-5, IL-10, IL-12, IL-13, IL-17, TNF and GM-CSF) had any predictive value regarding IVF outcome. The majority of the cytokines reached their peak levels at ovum pick-up, suggesting an enhancing influence of the hormonal stimulation. Pregnancy was associated with a high number of IL-4-, IL-5- and IL-13-secreting cells four weeks after ET. In conclusion, the results do not support our hypothesis of a more pronounced peripheral Th1 and Th17 deviation towards paternal antigens in infertile women with an unsuccessful IVF outcome, although this is based on a small number of observations. A larger study is required to confirm this conclusion. Higher numbers of Th2-associated cytokine-secreting cells in pregnant women four weeks after ET do corroborate the hypothesis of a Th2 deviation during pregnancy.
    Journal of Reproductive Immunology 12/2012; 96(s 1–2):58–67. DOI:10.1016/j.jri.2012.07.005 · 2.37 Impact Factor
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    • "From the 1980s to the 1990s, maternal tolerance to alloantigens was explained by the predominance of Th2 immunity over Th1 immunity, which protected the fetus from maternal " attack " . Th1 predominance was observed in cases of recurrent [18] [19] and spontaneous [18] [20] miscarriages and preeclampsia [18] [21]. However, the predominance of Th2 immunity was also reported in cases of recurrent miscarriages [18] [22]; therefore, the Th1/Th2 paradigm is also insufficient to explain the mechanism that prevents the rejection of the fetal allograft. "
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    ABSTRACT: The purpose of this study was to review the literature regarding the action of the cytokines interleukin 10 (IL-10) and tumor necrosis factor-alpha (TNF-α) in pregnancy and to emphasize the factors that are of interest to clinical obstetrics. The literature highlights several actions of IL-10 and TNF-α during pregnancy. The actions of these cytokines seem to be antagonistic and dependent on the balance between them, which is orchestrated by the specific immunosuppressive action of IL-10. TNF-α has a characteristic inflammatory action, and it is an additional diabetogenic factor in pregnancy. The loss of the control of the production of these cytokines, with increase of TNF-α, is related to the risk for developing obstetric complications, particularly recurrent fetal loss, gestational diabetes mellitus, hypertensive syndromes, and fetal growth restriction. However, study results are controversial and are not clearly defined. These issues are attributed to the heterogeneity of the studies, particularly regarding their sample sizes and sources, the evaluation methods, and the multiplicity of factors and conditions that influence cytokine production. These questions are fundamental and should be addressed in future investigations to obtain more consistent results that can be applied to obstetric practice.
    ISRN obstetrics and gynecology 02/2012; 2012:230742. DOI:10.5402/2012/230742
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