Donor Treg expansion by liposomal α-galactosylceramide modulates Tfh cells and prevents sclerodermatous chronic graft-versus-host disease

Hiroyuki Sugiura, Ken ichi Matsuoka, Takuya Fukumi, Yuichi Sumii, Takumi Kondo, Shuntaro Ikegawa, Yusuke Meguri, Miki Iwamoto, Yasuhisa Sando, Makoto Nakamura, Tomohiro Toji, Yasuyuki Ishii, Yoshinobu Maeda

Research output: Contribution to journalArticlepeer-review

Abstract

Background and Aim: Chronic graft-versus-host disease (cGVHD) is a major cause of nonrelapse morbidity and mortality following hematopoietic stem cell transplantation (HSCT). α-Galactosylceramide (α-GC) is a synthetic glycolipid that is recognized by the invariant T-cell receptor of invariant natural killer T (iNKT) cells in a CD1d-restricted manner. Stimulation of iNKT cells by α-GC leads to the production of not only immune-stimulatory cytokines but also immune-regulatory cytokines followed by regulatory T-cell (Treg) expansion in vivo. Methods: We investigated the effect of iNKT stimulation by liposomal α-GC just after transplant on the subsequent immune reconstitution and the development of sclerodermatous cGVHD. Results: Our study showed that multiple administrations of liposomal α-GC modulated both host- and donor-derived iNKT cell homeostasis and induced an early expansion of donor Tregs. We also demonstrated that the immune modulation of the acute phase was followed by the decreased levels of CXCL13 in plasma and follicular helper T cells in lymph nodes, which inhibited germinal center formation, resulting in the efficient prevention of sclerodermatous cGVHD. Conclusions: These data demonstrated an important coordination of T- and B-cell immunity in the pathogenesis of cGVHD and may provide a novel clinical strategy for the induction of immune tolerance after allogeneic HSCT.

Original languageEnglish
Pages (from-to)721-733
Number of pages13
JournalImmunity, inflammation and disease
Volume9
Issue number3
DOIs
Publication statusPublished - Sep 2021
Externally publishedYes

Keywords

  • Tfh cells
  • chronic graft-versus-host disease
  • hematopoietic stem cell transplantation
  • iNKT cells
  • regulatory T cells
  • α-galactosylceramide

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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