IFN-λ therapy prevents severe gastrointestinal graft-versus-host disease

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.

Automated summary

The text discusses the importance of immunopathology and intestinal stem cell loss in graft-versus-host disease, as well as interferon-lambda as a key protective factor. Research shows that intervention with interferon-lambda can prevent the loss of intestinal stem cells and improve the condition of GVHD.