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-lambda (IFNl, IL-28/IL-29) as a key protector of GI GVHD immunopathology, notably within the intestinal stem cell (ISC) compartment. Ifnlr1-/- mice displayed exaggerated GI GVHD and mortality independent of Paneth cells and alterations to microbiome. Ifnlr1-/- intestinal organoid growth was significantly impaired and targeted Ifnlr1 deficiency demonstrated effects intrinsic to recipient Lgr5+ ISC and NK cells. PEGylated IL-29 (PEG-rIL-29) treatment of naïve mice enhanced Lgr5+ ISC numbers and organoid growth independent of both IL-22 and type-1 IFN and modulated proliferative and apoptosis gene sets in Lgr5+ ISC. 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 IFNl,-signaling in recipient NK cells. IFNl is therefore an attractive and rapidly testable approach to prevent ISC loss and immunopathology during GVHD.
Andrea S Henden, Motoko Koyama, Renee J Robb, Adriana Forero, Rachel D Kuns, Karshing Chang, Kathleen S Ensbey, Antiopi Varelias, Stephen H Kazakoff, Nicola Waddell, Andrew D Clouston, Rabina Giri, Jakob Begun, Bruce R Blazar, Mariapia A Degli-Esposti, Sergei V Kotenko, Steven W Lane, Kate Bowerman, Ram Savan, Philip Hugenholtz, Kate H Gartlan, Geoffrey R Hill