title: IL-35 mitigates murine acute graft-versus-host disease with retention of graft-versus-leukemia effects.
abstract: IL-35 is a newly discovered inhibitory cytokine secreted by regulatory T cells (Tregs) and may have therapeutic potential in several inflammatory disorders. Acute graft-versus-host disease (aGVHD) is a major complication of allogeneic hematopoietic stem cell transplantation and caused by donor T cells and inflammatory cytokines. The role of IL-35 in aGVHD is still unknown. Here we demonstrate that IL-35 overexpression suppresses CD4(+) effector T-cell activation, leading to a reduction in alloreactive T-cell responses and aGVHD severity. It also leads to the expansion of CD4(+)Foxp3(+) Tregs in the aGVHD target organs. Furthermore, IL-35 overexpression results in a selective decrease in the frequency of Th1 cells and an increase of IL-10-producing CD4(+) T cells in aGVHD target tissues. Serum levels of TNF-α, IFN-γ, IL-6, IL-22 and IL-23 decrease and IL-10 increases in response to IL-35. Most importantly, IL-35 preserves graft-versus-leukemia effect. Finally, aGVHD grade 2-4 patients have decreased serum IL-35 levels comparing with time-matched patients with aGVHD grade 0-1. Our findings indicate that IL-35 has an important role in reducing aGVHD through promoting the expansion of Tregs and repressing Th1 responses, and should be investigated as the therapeutic strategy for aGVHD.
authors.affiliation: Laboratory of Cellular and Molecular Tumor Immunology, Cyrus Tang Hematology Center, Department of Hematology, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Laboratory of Cellular and Molecular Tumor Immunology, Cyrus Tang Hematology Center, Department of Hematology, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Laboratory of Cellular and Molecular Tumor Immunology, Cyrus Tang Hematology Center, Department of Hematology, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Cai
authors.affiliation: Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.
authors.forename: B
authors.initials: B
authors.lastname: Hu
authors.affiliation: Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.
authors.forename: G
authors.initials: G
authors.lastname: Bao
authors.affiliation: Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.
authors.forename: H
authors.initials: H
authors.lastname: Fang
authors.affiliation: Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.
authors.forename: L
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.
authors.forename: S
authors.initials: S
authors.lastname: Ma
authors.affiliation: Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Cheng
authors.affiliation: Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Song
authors.affiliation: Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Laboratory of Cellular and Molecular Tumor Immunology, Cyrus Tang Hematology Center, Department of Hematology, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Zhu
authors.affiliation: Laboratory of Cellular and Molecular Tumor Immunology, Cyrus Tang Hematology Center, Department of Hematology, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China.
authors.forename: H
authors.initials: H
authors.lastname: Chang
authors.affiliation: Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.
authors.forename: X
authors.initials: X
authors.lastname: Yu
authors.affiliation: Laboratory of Cellular and Molecular Tumor Immunology, Cyrus Tang Hematology Center, Department of Hematology, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China.
authors.forename: A
authors.initials: A
authors.lastname: Sun
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: D A A
authors.initials: DA
authors.lastname: Vignali
authors.affiliation: Laboratory of Cellular and Molecular Tumor Immunology, Cyrus Tang Hematology Center, Department of Hematology, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China.
authors.forename: D
authors.initials: D
authors.lastname: Wu
authors.affiliation: 1] Laboratory of Cellular and Molecular Tumor Immunology, Cyrus Tang Hematology Center, Department of Hematology, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China [2] Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.
authors.forename: H
authors.initials: H
authors.lastname: Liu
mesh_terms: D000208:Acute Disease; D000818:Animals; D049109:Cell Proliferation; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D006086:Graft vs Host Disease / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D020544:Graft vs Leukemia Effect / Q000276:immunology*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology; D053759:Interleukin-23 / Q000235:genetics / Q000276:immunology; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology; D007378:Interleukins / Q000235:genetics / Q000276:immunology*; D007938:Leukemia / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology; D000097043:Interleukin-22
chemical_list: D007371:Interferon-gamma; D016753:Interleukin-10; D053759:Interleukin-23; D015850:Interleukin-6; D007378:Interleukins; D014409:Tumor Necrosis Factor-alpha; D000097043:Interleukin-22; C556062:IL10 protein, mouse; C569375:interleukin-35, mouse