| First Author | Henden AS | Year | 2021 |
| Journal | Blood | Volume | 138 |
| Issue | 8 | Pages | 722-737 |
| PubMed ID | 34436524 | Mgi Jnum | J:315686 |
| Mgi Id | MGI:6829574 | Doi | 10.1182/blood.2020006375 |
| Citation | Henden AS, et al. (2021) IFN-lambda therapy prevents severe gastrointestinal graft-versus-host disease. Blood 138(8):722-737 |
| abstractText | 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 (IFN-lambda; 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-lambda-signaling in recipient natural killer cells. IFN-lambda is therefore an attractive and rapidly testable approach to prevent ISC loss and immunopathology during GVHD. |
