Immunopathology and intestinal stem cell (ISC) loss in the gastrointestinal (GI) tract is the prima facie manifestation of graft-versus-host disease (GVHD) and is responsible for significant mortality after allogeneic bone marrow transplantation (BMT). Approaches to prevent GVHD to date focus on immune suppression. Here, we identify interferon-λ (IFN-λ; interleukin-28 [IL-28]/IL-29) as a key protector of GI GVHD immunopathology, notably within the ISC compartment. Ifnlr1−/− mice displayed exaggerated GI GVHD and mortality independent of Paneth cells and alterations to the microbiome. Ifnlr1−/− intestinal organoid growth was significantly impaired, and targeted Ifnlr1 deficiency exhibited effects intrinsic to recipient Lgr5+ ISCs and natural killer cells. PEGylated recombinant IL-29 (PEG-rIL-29) treatment of naive mice enhanced Lgr5+ ISC numbers and organoid growth independent of both IL-22 and type I IFN and modulated proliferative and apoptosis gene sets in Lgr5+ ISCs. PEG-rIL-29 treatment improved survival, reduced GVHD severity, and enhanced epithelial proliferation and ISC-derived organoid growth after BMT. The preservation of ISC numbers in response to PEG-rIL-29 after BMT occurred both in the presence and absence of IFN-λ–signaling in recipient natural killer cells. IFN-λ is therefore an attractive and rapidly testable approach to prevent ISC loss and immunopathology during GVHD.
Bibliographical noteFunding Information:
The authors thank Leanne Cooper for her assistance in preparation of samples for RNAseq and the QIMR Berghofer Medical Research Institute Core Flow Cytometry and Histology departments. A.S.H. was supported by a Leukemia Foundation clinical scholarship, The Royal Brisbane and Women's Hospital (RBWH) Foundation, and a Haematology Society of Australia and New Zealand New Investigator Scholarship. The experimental work was supported by grants from the National Health and Medical Research Council (APP1146859). B.R.B. was supported by that National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute (R01 HL56067 and R01 HL155114) and the NIH/National Institute of Allergy and Infectious Diseases (R37 AI34495). G.R.H. was supported by the NIH/National Heart, Lung, and Blood Institute (R01 HL148164). Experimental histopathology at Fred Hutchinson Cancer Research Center was supported by the NIH/National Cancer Institute (P30 CA015704). Scientific Computing Infrastructure at Fred Hutchinson Cancer Research Center was supported by Office of Research Infrastructure Programs (ORIP) grant S10OD028685.
Conflict-of-interest disclosure: A.S.H., M.K., K.H.G., and G.R.H. are inventors on patents describing methods to attenuate immune pathology in the GI tract that includes IFN-λ. S.V.K. is an inventor on patents and patent applications related to IFN-λs, which have been licensed for commercial development. G.R.H. has consulted for Generon Corporation and NapaJen Pharma; and receives research funding from Compass Therapeutics, Syndax Pharmaceuticals, Applied Molecular Transport, and iTeos Therapeutics. B.R.B. receives remuneration as an advisor to Magenta Therapeutics and BlueRock Therapeutics; research funding from BlueRock Therapeutics and Rheos Medicines; and is a co-founder of Tmunity Therapeutics. K.H.G. has consulted for, and receives research funding, from CSL Ltd. The remaining authors declare no competing financial interests.
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