{"doi":"10.1182/blood.2020006375","title":"IFN-λ therapy prevents severe gastrointestinal graft-versus-host disease","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.","journal":"Blood","year":2021,"id":166194,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":34,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9619,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":690983,"name":"Motoko Koyama","orcid":"0000-0001-9169-9360","position":1,"is_corresponding":false},{"id":691730,"name":"Renee J. 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Kotenko","orcid":"0000-0001-5694-878X","position":15,"is_corresponding":false},{"id":302697,"name":"Steven Lane","orcid":"0000-0002-8050-6209","position":16,"is_corresponding":false},{"id":690985,"name":"Kate L Bowerman","orcid":"0000-0003-2339-114X","position":17,"is_corresponding":false},{"id":335067,"name":"Ram Savan","orcid":"0000-0002-3087-1355","position":18,"is_corresponding":false},{"id":19795,"name":"Philip Hugenholtz","orcid":"0000-0001-5386-7925","position":19,"is_corresponding":false},{"id":690986,"name":"Kate H. Gartlan","orcid":"0000-0002-0343-1274","position":20,"is_corresponding":false},{"id":242760,"name":"Geoffrey R. 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