Abstract

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.

Authors	Henden, Andrea S; Koyama, Motoko; Robb, Renee J; Forero, Adriana; Kuns, Rachel D; Chang, Karshing; Ensbey, Kathleen S; Varelias, Antiopi; Kazakoff, Stephen H; Waddell, Nicola; Clouston, Andrew D; Giri, Rabina; Begun, Jakob; Blazar, Bruce R; Degli-Esposti, Mariapia A; Kotenko, Sergei V; Lane, Steven W; Bowerman, Kate; Savan, Ram; Hugenholtz, Philip; Gartlan, Kate H; Hill, Geoffrey R
Journal	BLOOD
Pages	722-737
Volume	138
Date	1/01/2021
Grant ID
Funding Body
URL	http://www.ncbi.nlm.nih.gov/pubmed/?term=10.1182/blood.2020006375