Acute graft-versus-host disease (aGVHD), mediated by the recognition of host major histocompatibility complex/peptide polymorphisms by donor T cells, remains a significant complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). aGVHD most commonly involves the gastrointestinal tract, liver, and skin; symptomatic aGVHD is treated with corticosteroids. Steroid-nonresponsive aGVHD is a significant problem for patients undergoing allo-HSCT, with <15% of these patients alive 1 year after diagnosis. Previously, we found that the infusion of donor innate lymphoid type 2 (ILC2) cells could prevent and treat aGVHD of the lower gastrointestinal tract with no effect on the graft-versus-leukemia response. This approach for clinical translation is cumbersome, as it would require the generation of donor-derived ILC2 cells for each recipient. Thus, the ability to use third-party ILC2 cells would provide an "off-the-shelf" reagent that could be used to treat and/or prevent aGVHD. Here, we show that third-party ILC2 cells enhance the survival of allo-HSCT recipients. Treatment required at least 4 weekly infusions of ILC2 cells. Mechanistically, we show that ILC2 cell function was completely lost if the cells could not express both interleukin-13 (IL-13) and amphiregulin. Finally, we show that the activity of IL-13 has a greater dependence on the expression of the IL-13R on host rather than donor bone marrow cells. The ability to generate third-party ILC2 cells offers a new avenue for the prevention of aGVHD.
Bibliographical noteFunding Information:
This work was supported by the National Institutes of Health, National Heart, Lung, and Blood Institute (RO1 HL139730, J.S.S.; R01 HL155098, J.S.S.; R01 HL56067, B.R.B.; and R01 HL11879, B.R.B.), National Institute of Allergy and Infectious Diseases (R37 AI34495, B.R.B.), and National Cancer Institute (P01 CA065493, H.S. and B.R.B.). It was also supported by a TRP Grant from the Leukemia and Lymphoma Society (J.S.S. and B.R.B.).
Conflict-of-interest disclosure: B.R.B. receives remuneration as an advisor to Magenta Therapeutics and BlueRock Therapeutics; research funding from BlueRock Therapeutics, Rheos Medicines, Equilibre Biopharmaceuticals, and Carisma Therapeutics, Inc.; and is a cofounder of Tmunity Therapeutics and an inventor on a pending patent application for use of ILC2s in GVHD. J.S.S. is supported by grants from Merck Sharpe & Dohme, Carisma Therapeutics, and GlaxoSmithKline. He has filed for intellectual property for the use of ILCs to treat and/or prevent aGVHD. D.W.B., H.S., and J.M.C. have filed for intellectual property for the use of ILCs to treat and/or prevent aGVHD. The remaining authors declare no competing financial interests.
ß 2021 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.
- Gastrointestinal Tract
- Graft vs Host Disease/prevention & control
- Hematopoietic Stem Cell Transplantation/adverse effects
- Immunity, Innate
PubMed: MeSH publication types
- Research Support, Non-U.S. Gov't
- Journal Article
- Research Support, N.I.H., Extramural