Cyclosporine A improves pregnancy outcomes in women with recurrent pregnancy loss and elevated Th1/Th2 ratio

Azizi, Ramyar; Ahmadi, Majid; Danaii, Shahla; Abdollahi‐Fard, Sedigheh; Mosapour, Parisa; Eghbal‐Fard, Shadi; Kamrani, Amin; Rahnama, Badrossadat; Mehdizadeh, Amir; Jadidi‐Niaragh, Farhad; Yousefi, Bahman; Yousefi, Mehdi

doi:10.1002/jcp.28543

Cited by 46 publications

(39 citation statements)

References 38 publications

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“…The overall alternation of all immunological parameters among the three groups was shown in Figure 1B. Previous studies reported that CD4 + T cells biased to Th2 and/or Treg cells, focusing mainly on the Th1/Th2 and Th17/Treg balance, promote the development of normal pregnancy (26)(27)(28). Although recent advances in reproductive immunology have expanded the Th1/Th2/Th17/Treg paradigm to the Th1/Th2/Th9/Th17/Th22/follicular T helper (Tfh) paradigm ( 29), this could not uncover the whole knowledge of the immunological factors in RPL.…”

Section: Significantly Changed Immune Parameters Related To Rplmentioning

confidence: 79%

Systemic Characterization of Novel Immune Cell Phenotypes in Recurrent Pregnancy Loss

et al. 2021

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Recurrent pregnancy loss (RPL) is a disturbing disease in women, and 50% of RPL is reported to be associated with immune dysfunction. Most previous studies of RPL focused mainly on the relationship between RPL and either T cells or natural killer (NK) cells in peripheral blood and the decidua; few studies presented the systemic profiles of the peripheral immune cell subsets in RPL women. Herein, we simultaneously detected 63 immune cell phenotypes in the peripheral blood from nonpregnant women (NPW), women with a history of normal pregnancy (NP) and women with a history of RPL (RPL) by multi-parameter flow cytometry. The results demonstrated that the percentages of naïve CD4+ T cells, central memory CD4+ T cells, naïve CD8+ T cells, mature NK cells, Vδ1+ T cells and the ratio of Vδ1+ T cells/Vδ2+ T cells were significantly higher in the RPL group than those in the NPW and NP groups, whereas the percentages of terminal differentiated CD4+ T cells, effective memory CD4+ T cells, immature NK cells and Vδ2+ T cells were significantly lower in the RPL group than those in the NPW and NP groups. Interestingly, we found that peripheral T helper (TPH) cells were more abundant in the NPW group than in the NP and RPL groups. Moreover, the percentage of Vδ2+PD-1+ gamma-delta (γδ) T cells was extremely high, above the 95th percentile limit, in the NP group compared with the NPW and RPL groups, which has never been reported before. In addition, we also determined the 5th percentile lower limit and 95th percentile upper limit of the significantly changed immunological parameters based on the files of the NPW group. Taken together, this is the first study to simultaneously characterize the multiple immune cell subsets in the peripheral blood at a relatively large scale in RPL, which might provide a global readout of the immune status for clinicians to identify clinically-relevant immune disorders and guide them to make clear and individualized advice and treatment plans.

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Section: Significantly Changed Immune Parameters Related To Rplmentioning

confidence: 79%

Systemic Characterization of Novel Immune Cell Phenotypes in Recurrent Pregnancy Loss

et al. 2021

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“…Although only eight women had a high Th1/Th2 cell ratio (>11.8, average +1SD), seven women (87.5%) including three with an abnormally elevated Th1/Th2 cell ratio (>15.3, average +2SD) conceived and had babies without any immune modulation therapy. According to previous reports, no RIF women with high Th1/Th2 cell ratios achieved a pregnancy without immunotherapy and livebirth rates in the RPL women with high Th1/Th2 cell ratios were only 40%‐45% 12,19,20 . Therefore, Th cell testing and immunological therapy may not be necessary in general infertile women.…”

Section: Discussionmentioning

confidence: 98%

“…Successful pregnancy requires a balance of pro‐ and anti‐inflammation‐related cytokines, which are secreted by Th1 and Th2 cells, respectively, with the importance initially of pro‐inflammatory cytokines, subsequent regulation by T regulatory cells via HLA and soluble hCG and then a Th2 dominance 10,11 . There is insufficient evidence on the modulation of an imbalanced Th1/Th2 cell ratio for RIF and RPL 14 ; however, therapeutic effects of optimizing the Th1/Th2 cell imbalance via immunotherapy have been reported in patients with a history of RIF and RPL 12,15–21 …”

Section: Introductionmentioning

confidence: 99%

Increasing number of implantation failures and pregnancy losses associated with elevated Th1/Th2 cell ratio

Kuroda

Nakagawa²,

Horikawa³

et al. 2021

American J Rep Immunol

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Problem We aimed to assess whether an imbalance of T‐helper (Th) 1 and Th2 cells contributes to implantation failure and pregnancy loss. Method of study In this cross‐sectional study, 197 consecutive patients with a history of repeated implantation failure (RIF) after three or more embryo transfer (ET) cycles and/or recurrent pregnancy loss (RPL) after two or more clinical pregnancy losses underwent Th cell testing. After excluding 42 women aged ≥44 and 9 with vitamin D supplementation, we recruited 146 women including 79 with RIF and 81 with RPL. Fourteen women had a history of both RIF and RPL. We also recruited 45 fertile women and 40 general infertile women without a history of in vitro fertilization treatment. This study was approved by the local ethics committee. Results There was no significant difference in IFN‐γ‐producing Th1 and IL‐4‐producing Th2 cell levels between the fertile and general infertile women, but Th1 cell levels and the Th1/Th2 cell ratio were significantly higher in the women with ≥4 ET cycles and ≥2 pregnancy losses than in the fertile and general infertile women. In the general infertile women, the total livebirth rates including natural conception after two ET cycles in the normal and high Th1/Th2 groups (Th1/Th2 <11.8 and ≥11.8, respectively) were 66.7% and 87.5%, respectively (p = .395). Conclusions A high Th1/Th2 cell ratio was linked to ≥4 implantation failure cycles and ≥2 pregnancy losses but not to general infertility.

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“…An appropriate dose of CsA (from 80 ng/ml to 150 ng/ ml) produces good curative effects and, in pregnancy, is used to treat immunity-related recurrent spontaneous abortion [23]. A low-dose CsA (150 mg/day) treatment for 6 months improves pregnancy outcomes in women with recurrent pregnancy loss and an elevated Th1/Th2 ratio [24]. Low-dose CsA (100 mg/day) treatment for 30 days increases the live birth rate for women with unexplained recurrent abortion, and it produces no obvious side effects or adverse consequences [25].…”

Section: Discussionmentioning

confidence: 99%

Cyclosporin A protects JEG-3 cells against oxidative stress-induced apoptosis by inhibiting the p53 and JNK/p38 signaling pathways

et al. 2020

Reprod Biol Endocrinol

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Background Trophoblast cells are required for the establishment of pregnancy and fetal development. Apoptosis is an essential feature for trophoblast invasion. Uncontrolled trophoblast apoptosis is related to some complicate pregnancies. Oxidative stress (OS) is an important inducer of trophoblast apoptosis. Cyclosporin A (CsA) has been shown to promote the activity of trophoblast cells and reduce OS-induced oxidative injury. We investigated the role and mechanism of CsA in oxidative stress-induced trophoblast cell apoptosis. Methods JEG-3 cells were cocultured with H2O2 and CsA. Cell viability and morphology were measured by MTT assay and DAPI staining. Cell apoptosis was tested with annexin V/PI staining. The expression of Bcl-2-associated X protein (Bax), B-cell lymphoma/leukemia-2 (Bcl-2), cleaved poly (ADP-ribose) polymerase (PARP) and pro-caspase-3 was assayed by western blotting. The protein expression and phosphorylation of p53 and mitogen-activated protein kinase (MAPK) kinases (JNK, ERK1/2 and p38) were examined by western blotting. Results CsA increased the viability, alleviated morphological injury and reduced cell apoptosis of the H2O2-treated JEG-3 cells. CsA also attenuated the activation of p53, decreased the expression of Bax and cleavage of PARP, and increased the expression of Bcl-2 and pro-caspase-3 in the JEG-3 treated with H2O2. Furthermore, CsA reduced the activation of JNK and P38 but had no significant effect on the activation of extracellular signal-regulated kinase 1/2 (ERK1/2) in the H2O2-treated JEG-3 cells. Promoting the activation of JNK and p38 impaired the protective effect of CsA on OS-induced trophoblast apoptosis. Conclusions These results suggested that CsA protected trophoblast cells from OS-induced apoptosis via the inhibition of the p53 and JNK/p38 signaling pathways.

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Cyclosporine A improves pregnancy outcomes in women with recurrent pregnancy loss and elevated Th1/Th2 ratio

Cited by 46 publications

References 38 publications

Systemic Characterization of Novel Immune Cell Phenotypes in Recurrent Pregnancy Loss

Systemic Characterization of Novel Immune Cell Phenotypes in Recurrent Pregnancy Loss

Increasing number of implantation failures and pregnancy losses associated with elevated Th1/Th2 cell ratio

Cyclosporin A protects JEG-3 cells against oxidative stress-induced apoptosis by inhibiting the p53 and JNK/p38 signaling pathways

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