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

Author:

Henden Andrea S.123ORCID,Koyama Motoko4,Robb Renee J.1,Forero Adriana5ORCID,Kuns Rachel D.1,Chang Karshing1,Ensbey Kathleen S.4,Varelias Antiopi1ORCID,Kazakoff Stephen H.6ORCID,Waddell Nicole6,Clouston Andrew D.7,Giri Rabina8,Begun Jakob8ORCID,Blazar Bruce R.9ORCID,Degli-Esposti Mariapia A.1011,Kotenko Sergei V.1213ORCID,Lane Steven W.14ORCID,Bowerman Kate L.15ORCID,Savan Ram5,Hugenholtz Philip15,Gartlan Kate H.13ORCID,Hill Geoffrey R.1416

Affiliation:

1. Bone Marrow Transplantation Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia;

2. Department of Haematology and Bone Marrow Transplantation, Royal Brisbane and Women’s Hospital, Brisbane, QLD, Australia;

3. Faculty of Medicine, The University of Queensland, Herston, QLD, Australia;

4. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA;

5. Center for Innate Immunity and Immune Disease, University of Washington, Seattle, WA;

6. Genetics and Computational Biology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia;

7. Envoi Pathology, Brisbane, QLD, Australia;

8. Mater Research Institute, The University of Queensland–Translational Research Institute, Brisbane, QLD, Australia;

9. Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, MN;

10. Centre for Experimental Immunology, Lions Eye Institute, Perth, WA, Australia;

11. Infection and Immunity Program, Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia;

12. Center for Immunity and Inflammation, New Jersey Medical School, and

13. Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers Biomedical and Health Sciences (RBHS), Newark, NJ;

14. Cancer Program, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia;

15. Australian Centre for Ecogenomics, School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD, Australia; and

16. Division of Medical Oncology, The University of Washington, Seattle, WA

Abstract

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-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.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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