High doses of intravenous immunoglobulin stimulate regulatory T cell and suppress natural killer cell in women with recurrent pregnancy loss

Hideto Yamada; Masashi Deguchi; Shigeru Saito; Toshiyuki Takeshita; Mari Mitsui; Tsuyoshi Saito; Takeshi Nagamatsu; Koichi Takakuwa; Mikiya Nakatsuka; Satoshi Yoneda; Katsuko Egashira; Masahito Tachibana; Keiichi Matsubara; Ritsuo Honda; Atsushi Fukui; Kanji Tanaka; Kazuo Sengoku; Toshiaki Endo; Hiroaki Yata

doi:10.1016/j.jri.2023.103977

High doses of intravenous immunoglobulin stimulate regulatory T cell and suppress natural killer cell in women with recurrent pregnancy loss

J Reprod Immunol. 2023 Aug:158:103977. doi: 10.1016/j.jri.2023.103977. Epub 2023 Jun 14.

Authors

Hideto Yamada¹, Masashi Deguchi², Shigeru Saito³, Toshiyuki Takeshita⁴, Mari Mitsui⁵, Tsuyoshi Saito⁶, Takeshi Nagamatsu⁷, Koichi Takakuwa⁸, Mikiya Nakatsuka⁹, Satoshi Yoneda³, Katsuko Egashira¹⁰, Masahito Tachibana¹¹, Keiichi Matsubara¹², Ritsuo Honda¹³, Atsushi Fukui¹⁴, Kanji Tanaka¹⁵, Kazuo Sengoku¹⁶, Toshiaki Endo⁶, Hiroaki Yata¹⁷

Affiliations

¹ Center for Recurrent Pregnancy Loss, Teine Keijinkai Hospital, 1-40 Maeda 1-jho 12-chome Teine-ku, Sapporo, Japan. Electronic address: yamada-hideto@keijinkai.or.jp.
² Department of Obstetrics and Gynecology, Kobe University School of Medicine, 7-5-1 Kusunoki-cho Chuo-ku, Kobe, Japan.
³ Department of Obstetrics and Gynecology, The Toyama University, 2630 Sugitani, Toyama, Japan.
⁴ Department of Obstetrics and Gynecology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, Japan.
⁵ Division of Reproductive Medicine and Maternal Care, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo, Japan.
⁶ Department of Obstetrics and Gynecology, Sapporo Medical University, Minami 1-jo Nishi 17-chome, Chuo-ku, Sapporo, Japan.
⁷ Department of Obstetrics and Gynecology, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan.
⁸ Niigata University, 1-757 Asahimachi-dori, Chuo-ku, Niigata, Japan.
⁹ Okayama University, Graduate School of Health Sciences, 2-5-1 Shikata, Kita-ku, Okayama, Japan.
¹⁰ Department of Obstetrics and Gynecology, Hamanomachi Hospital, 3-3-1 Nagahama, Chuo-ku, Fukuoka, Japan.
¹¹ Department of Obstetrics and Gynecology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Japan.
¹² Department of Obstetrics and Gynecology, Ehime University School of Medicine, 454 Shitsukawa, Toon, Japan.
¹³ Department of Obstetrics and Gynecology, Kumamoto University School of Medicine, 1-1-1 Honjo, Chuo-ku, Kumamoto, Japan.
¹⁴ Department of Obstetrics and Gynecology, Hyogo Medical University School of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Japan.
¹⁵ Department of Obstetrics and Gynecology, Hirosaki University School of Medicine, 53 Honcho, Hirosaki, Japan.
¹⁶ Department of Obstetrics and Gynecology, Asahikawa Medical University, 1-1-1 Midorigaoka-higashi 2-jo, Asahikawa, Japan.
¹⁷ Research & Development Division, Japan Blood Products Organization, 15F Tamachi Station Tower N 3-1-1 Shibaura, Minato-ku, Tokyo, Japan.

PMID: 37354783
DOI: 10.1016/j.jri.2023.103977

Abstract

The aim was to evaluate whether natural killer (NK) cells and regulatory T (Treg) cells were involved in mechanisms underlying beneficial effects of a high dose of intravenous immunoglobulin (IVIG) on recurrent pregnancy losses (RPL) of unexplained etiology. In a double-blind, randomized, placebo-controlled trial of IVIG (400 mg/kg, for 5 days in 4-6 weeks of gestation) in women with RPL, blood samples were collected pre-infusion, one week after infusion (1 w), and eight weeks of gestation/when miscarried (8 w). Levels of NK and Treg cells in peripheral blood were compared between women with IVIG (n = 50) and placebo (n = 49), and between women with IVIG who gave live birth (n = 29) and those who had miscarriage with normal chromosome (n = 12). Effector Treg cell percentages in IVIG group at 1 w (mean 1.43 % vs. 1.03 %) and at 8 w (1.91 % vs. 1.18 %) were higher than those in placebo group (p < 0.01). Total Treg cell percentages in IVIG group at 1 w (4.75 % vs. 4.08 %) and at 8 w (5.55 % vs. 4.47 %) were higher than those in placebo group (p < 0.05). In women with live birth, total Treg cell percentages increased at 8 w (5.52 %, p < 0.001) compared with pre-infusion (4.54 %) and 1 w (4.47 %), while NK cell activity decreased at 1 w (20.18 %, p < 0.001) compared with pre-infusion (26.59 %). IVIG increased Treg cell percentages and suppressed NK cell activity very early in pregnancy, and these were associated with subsequent live birth. Stimulation of Treg cells and suppression of NK cell activity very early in pregnancy may be a mechanism of pharmacological effects of high dose IVIG.

Keywords: Intravenous immunoglobulin; Natural killer cell; Recurrent miscarriage; Recurrent pregnancy loss; Regulatory T cell.

Publication types

Randomized Controlled Trial
Research Support, Non-U.S. Gov't

MeSH terms

Abortion, Habitual*
Female
Humans
Immunoglobulins, Intravenous* / therapeutic use
Killer Cells, Natural
Pregnancy
Pregnancy Outcome
T-Lymphocytes, Regulatory

Substances

Immunoglobulins, Intravenous