Regulatory T cells improve pregnancy rate in RIF patients after additional IVIG treatment

ABSTRACT

RIF (repeated implantation failure) women with immunologic basis and cellular abnormalities may benefit from intravenous immunoglobulins (IVIG) as an immunomodulator based on different studies. In this study, we evaluated the effect of IVIG on the frequency and function of Th17 and Treg cells, as two important subgroups of CD₄⁺ T cells in implantation and pregnancy rates. Seventy-two RIF patients with preconception Th1⁄Th2 ratio and natural killer (NK) cells frequency and activity elevation were selected and divided into two groups; 40 out of 72 received IVIG, aspirin, and heparin (anoxaparin) and constituted the treatment group and 32 patients received aspirin and heparin (anoxaparin) and no IVIG and were the control group. Th17, Treg frequency, transcription factors, cytokine gene expression, and cytokine secretion were evaluated by flow cytometry, real-time PCR, and ELISA, respectively. Post-treatment evaluation of the IVIG grouprevealed a significant increase in Treg associated parameters such as Treg frequency (p = 0.0186), Foxp3 (p = 0.0004), and cytokine mRNA levels (IL-10, p = 0.0058 and TGF- β, p = 0.0038), however, in the case of Th17, a significant difference was only observed in a reduction in the RORγt mRNA level (p = 0.0218). In conclusion, IVIG therapy may be a good choice in the treatment of implantation failure in RIF women especially with an immunologic basis, and may improve the implantation and pregnancy rate by affecting immunoregulatory mechanisms such as Tregs.

Abbreviations: RIF: repeated implantation failure; IVIG: intravenous immunoglobulin; Th17: T helper 17; Treg: T regulatory; NK cells: natural killer cells; PCR: polymerase chain reaction; ELISA: enzyme-linked immunosorbent assay; RORγt: RAR-related orphan receptor gamma; Foxp3: forkhead box protein P3; IL-17: interleukin-17; LMWH: low-molecular weight heparin; dNK: decidual NK cells

KEYWORDS:

• Implantation failure
• IVIG therapy
• T reg
• Th17

Declaration of interest

This study was supported by a grant of the Drug Applied Research Center of Tabriz University of Medical Sciences, Tabriz, Iran (grant number: 95/26). None of the authors has any potential financial conflict of interest related to this manuscript, and none are directly employed by or funded by the Government of Iran.

Additional information

Notes on contributors

Mehdi Yousefi

Contributed to study design, helped with data collection, and performed statistical analyses: MA; Wrote the paper, was responsible for manuscript revision, and helped with data collection: SA-V; Contributed to cell collection and helped with immunological tests: MG, SD; Participated in the final edition of the manuscript: LA-M; Responsible for subject selection, monitoring, and inpatient and outpatient care: LF, AG, KH; Contributed to flowcytometric analysis: VY; Contributed to study design: MN; Principal investigator of the clinical trial and contributed to study design: MY.