Activation of natural killer T cells enhances the function of regulatory T-cell therapy in suppressing murine GVHD.

Abstract

Cellular therapy with regulatory T cells (Tregs) has shown promising results for suppressing graft-versus-host disease (GVHD) while preserving graft vs tumor effects in animal models and phase 1/2 clinical trials. However, a paucity of Tregs in the peripheral blood makes it difficult to acquire sufficient numbers of cells and hampers further clinical application. Invariant natural killer T (iNKT) cells constitute another compartment of regulatory cells that ameliorate GVHD through activation of Tregs after their own activation with α-galactosylceramide (α-GalCer) or adoptive transfer. We demonstrate here that a single administration of α-GalCer liposome (α-GalCer-lipo) enhanced the in vivo expansion of Tregs after adoptive transfer in a murine GVHD model and improved therapeutic efficacy of Treg therapy even after injection of otherwise suboptimal cell numbers. Host iNKT cells rather than donor iNKT cells were required for GVHD suppression because the survival benefit of α-GalCer-lipo administration was not shown in the transplantation of cells from wild-type (WT) C57BL/6 mice into Jα18-/- iNKT cell-deficient BALB/c mice, whereas it was observed from Jα18-/- C57BL/6 donor mice into WT BALB/c recipient mice. The combination of iNKT cell activation and Treg adoptive therapy may make Treg therapy more feasible and safer by enhancing the efficacy and reducing the number of Tregs required.

• Authors: Toshihito Hirai, Po-Yu Lin, Federico Simonetta, Kristina Maas-Bauer, Mustafa Turkoz, Melissa Mavers, Jeanette Baker, Robert S Negrin
• Journal: Blood advances (Blood Adv) Vol. 5 Issue 11 Pg. 2528-2538 (06 08 2021) ISSN: 2473-9537 [Electronic] United States
• PMID: 34100904 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 by The American Society of Hematology.

Topics

• Animals
• Graft vs Host Disease (therapy)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Natural Killer T-Cells
• T-Lymphocytes, Regulatory