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

Zahra Bahrami-Asl; Laya Farzadi; Amir Fattahi; Mehdi Yousefi; Alicia Quinonero; Parvin Hakimi; Zeinab Latifi; Hamid Reza Nejabati; Tohid Ghasemnejad; Aydin Raei Sadigh; Mohammad Hassan Heidari; Mohammad Nouri; Marefat Ghaffari Novin; Francisco Dominguez

doi:10.1055/a-1056-3148

GebFra - DGGG-Gesellschaftsausgaben, Table of Contents

CC BY-NC-ND 4.0 · Geburtshilfe Frauenheilkd 2020; 80(08): 851-862
DOI: 10.1055/a-1056-3148

GebFra Science

Original Article

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

Tacrolimus verbessert die Implantationsrate bei Patientinnen mit einem erhöhten Verhältnis von T-Helferzellen des Typs 1 zum Typ 2 und wiederholtem Implantationsversagen

Zahra Bahrami-Asl

¹Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran

²Fundacion Instituto Valenciano de Infertilidad (FIVI), Instituto Universitario IVI (IUIVI), ISS LaFe, Valencia, Spain

,

Laya Farzadi

³Department of Reproductive Biology, School of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran

⁴Womenʼs Reproductive Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

,

Amir Fattahi

³Department of Reproductive Biology, School of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran

⁴Womenʼs Reproductive Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

,

Mehdi Yousefi

⁵Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran

,

Alicia Quinonero

²Fundacion Instituto Valenciano de Infertilidad (FIVI), Instituto Universitario IVI (IUIVI), ISS LaFe, Valencia, Spain

,

Parvin Hakimi

⁴Womenʼs Reproductive Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

,

Zeinab Latifi

⁶Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran

,

Hamid Reza Nejabati

⁶Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran

,

Tohid Ghasemnejad

⁷Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran

,

Aydin Raei Sadigh

⁶Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran

,

Mohammad Hassan Heidari

¹Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran

,

Mohammad Nouri

³Department of Reproductive Biology, School of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran

⁸Institute for Stem Cell and Regenerative Medicine, Tabriz University of Medical Sciences, Tabriz, Iran

,

Marefat Ghaffari Novin

¹Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran

,

Francisco Dominguez

²Fundacion Instituto Valenciano de Infertilidad (FIVI), Instituto Universitario IVI (IUIVI), ISS LaFe, Valencia, Spain

› Author Affiliations

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.

Zusammenfassung

Einleitung Da eine abnorme Immunantwort des Endometriums möglicherweise an der Pathogenese von wiederholtem Implantationsversagen (RIF) beteiligt ist, haben wir die Auswirkungen einer Tacrolimus-Behandlung auf das Endometrium von Patientinnen mit RIF untersucht.

Material und Methoden Eine klinische Studie wurde bei 10 RIF-Patientinnen mit einem erhöhten Verhältnis der T-Helferzellen des Typs 1 zum Typ 2 (Th1/Th2) durchgeführt. Alle in der Studie aufgenommenen Frauen hatten mindestens 3 erfolglose Implantationsversuche hinter sich. Die Exprimierung von p53, leukämiehemmendem Faktor (LIF), Interleukin (IL)-4, IL-10, IL-17 und Interferon gamma (IFN-γ) in der Gebärmutterschleimhaut dieser Patientinnen vor und nach der Behandlung mit Tacrolimus und der Zusammenhang zwischen diesen Faktoren und dem Outcome nach assistierten Reproduktionstechnologien (ART) wurden geprüft.

Ergebnisse Die Behandlung mit Tacrolimus führte zu einer signifikanten Steigerung der Exprimierung von LIF, IL-10 und IL-17, verringerte die Exprimierung von IL-4 und IFN-γ und senkte das Verhältnis von IFN-γ zu IL-10 bei Patientinnen mit RIF. Die Tacrolimus-Behandlung führte zu einer Implantationsrate von 40%, einer 50%igen klinischen Schwangerschaftsrate und einer Lebendgeburtentrate von 35% bei Patientinnen mit RIF und einem erhöhten Th1/Th2-Verhältnis. Es gab auch eine signifikante positive Korrelation zwischen den IL-10-Konzentrationen und der Implantationsrate.

Schlussfolgerungen Unsere Ergebnisse lassen darauf schließen, dass RIF-Patientinnen mit einem erhöhten Th1/Th2-Verhältnis geeignete Kandidaten für eine Behandlung mit Tacrolimus sein könnten und dass dieses Immunsuppressivum möglicherweise durch eine Hochregulierung von LIF, IL-10 und IL-17 seine Wirkung entfaltet.

Key words

repeated implantation failure - embryo implantation - tacrolimus - immune system - assisted reproductive technology (ART) - intracytoplasmic sperm injection (ICSI) - in vitro fertilization (IVF) - leukemia inhibitory factor (LIF) - interleukin (IL)-4, IL-10, IL-17 - interferon gamma (IFN-γ)

Schlüsselwörter

wiederholtes Implantationsversagen - Embryotransfer - Tacrolimus - Immunsystem - assistierte Reproduktionstechnologie (ART) - intrazytoplasmatische Spermieninjektion (ICSI) - In-vitro-Fertilisation (IVF) - leukämiehemmender Faktor (LIF) - Interleukin (IL)-4, IL-10, IL-17 - Interferon gamma (IFN-γ)

Full Text

References

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