Tacrolimus Improves the Implantation Rate in Patients with Elevated Th1/2 Helper Cell Ratio and Repeated Implantation Failure (RIF)

Abstract

Introduction An abnormal endometrial immune response is involved in the pathogenesis of repeated implantation failure (RIF), so we investigated the effectiveness of tacrolimus treatment on the endometrium of RIF patients. Materials and Methods Ten RIF patients with elevated T-helper 1/T-helper 2 (Th1/Th2) cell ratios were recruited into a clinical study. The expression of p53, leukemia inhibitory factor (LIF), interleukin (IL)-4, IL-10, IL-17, and interferon gamma (IFN-γ) in the endometrium of patients with and without tacrolimus treatment and the association of these factors with assisted reproductive technology (ART) outcomes were investigated. Results Tacrolimus significantly increased the expression of LIF, IL-10, and IL-17 and decreased the expression of IL-4, IFN-γ, and the IFN-γ/IL-10 ratio in RIF patients. Tacrolimus treatment resulted in an implantation rate of 40%, a clinical pregnancy rate of 50%, and a live birth rate of 35% in RIF patients with elevated Th1/Th2 ratios who had previously failed to become pregnant despite at least three transfers of embryos. We also found a significant positive correlation between IL-10 levels and the implantation rate. Conclusions Our findings suggest that RIF patients with a higher Th1/Th2 ratio could be candidates for tacrolimus therapy and that this immunosuppressive drug could be acting through upregulation of LIF, IL-10, and IL-17.

Individual dynamics of uterine natural killer cells in natural and stimulated cycles monitored using a new endometrial dating method

“…A lower proportion of uNK cells was detected in combination with up‐regulation of leukemia‐inhibiting factor (LIF), interleukin (IL)‐10, and IL‐17 in the cohort with tacrolimus treatment, resulting in an implantation rate of 40%. The quantity of uNK cells in the well‐defined and dated endometrium in the present study may therefore provide evidence regarding subfertility in patients 8 …”

“…The quantity of uNK cells in the well-defined and dated endometrium in the present study may therefore provide evidence regarding subfertility in patients. 8 King et al reported that natural killer (NK) cells are closely associated with trophoblast invasion. The physical proximity of uNK cells to trophoblasts, their precise up-regulation in density around the time of implantation, and their ability to release cytokines known to stimulate trophoblast development 2,9 all point to a key role of uNK cells in early pregnancy events.…”

“…The quantity of uNK cells in the well‐defined and dated endometrium in the present study may therefore provide evidence regarding subfertility in patients. 8 …”

Recent Advances in Immunotherapeutic Approaches for Recurrent Reproductive Failure

“…LIF, IL-10, and IL-17 expression were upregulated and IL-4, IFN-γ expression, and IFN-γ/IL-10 ratio were downregulated post-treatment. Moreover, rate of implantation, clinical pregnancy, and live birth were 40, 50, and 35% respectively, in RIF women without a history of previous successful pregnancy [219]. Considering the results of these studies, Th1/Th2 ratio may be a biomarker for predicting ART outcomes in RIF patients and selection of suitable candidates for tacrolimus administration.…”

Low-Dose Tacrolimus Promotes the Migration and Invasion and Nitric Oxide Production in the Human-Derived First Trimester Extravillous Trophoblast Cells In Vitro

“…We have previously shown that the use of a low-dose (0.1 mg/kg) tacrolimus (formerly known as FK506; a 822 kDa naturally occurring lipophilic macrolide lactone immunosuppressant that was first isolated from the soil bacterium Streptomyces tsukabaensis [ 19 ] restores placentation and prevents uterine SAR defects in a murine model of FGR and recurrent implantation failure [ 20 ]. Recently, tacrolimus has also been used to treat female infertility and prevent adverse pregnancy outcomes in women with recurrent pregnancy loss with elevated systemic Th1 (CD4+ IFNγ+): Th2 (CD4+IL4+) cell ratios [ 21 , 22 , 23 ]. The well-characterized mode of action of tacrolimus is the inhibition Ca ++ dependent activation of NFκB and the nuclear factor of activated T cells (NFAT) in T lymphocytes blocking T-cell receptor-mediated lymphokine gene transcription, degranulation, exocytosis and apoptosis [ 24 , 25 ].…”