title: Blockade of interleukin-27 signaling reduces GVHD in mice by augmenting Treg reconstitution and stabilizing Foxp3 expression.
abstract: Reestablishment of competent regulatory pathways has emerged as a strategy to reduce the severity of graft-versus-host disease (GVHD), and recalibrate the effector and regulatory arms of the immune system. However, clinically feasible, cost-effective strategies that do not require extensive ex vivo cellular manipulation have remained elusive. In the current study, we demonstrate that inhibition of the interleukin-27p28 (IL-27p28) signaling pathway through antibody blockade or genetic ablation prevented lethal GVHD in multiple murine transplant models. Moreover, protection from GVHD was attributable to augmented global reconstitution of CD4+natural regulatory T cells (nTregs), CD4+induced Tregs (iTregs), and CD8+iTregs, and was more potent than temporally concordant blockade of IL-6 signaling. Inhibition of IL-27p28 also enhanced the suppressive capacity of adoptively transferred CD4+nTregs by increasing the stability of Foxp3 expression. Notably, blockade of IL-27p28 signaling reduced T-cell-derived-IL-10 production in conventional T cells; however, there was no corresponding effect in CD4+or CD8+Tregs, indicating that IL-27 inhibition had differential effects on IL-10 production and preserved a mechanistic pathway by which Tregs are known to suppress GVHD. Targeting of IL-27 therefore represents a novel strategy for the in vivo expansion of Tregs and subsequent prevention of GVHD without the requirement for ex vivo cellular manipulation, and provides additional support for the critical proinflammatory role that members of the IL-6 and IL-12 cytokine families play in GVHD biology.
authors.affiliation: Department of Medicine.
authors.forename: Ludovic
authors.initials: L
authors.lastname: Belle
authors.affiliation: Department of Medicine.
authors.forename: Kimberle
authors.initials: K
authors.lastname: Agle
authors.affiliation: Department of Medicine.
authors.forename: Vivian
authors.initials: V
authors.lastname: Zhou
authors.affiliation: Department of Medicine.
authors.forename: Cheng
authors.initials: C
authors.lastname: Yin-Yuan
authors.affiliation: Department of Pathology, and.
authors.forename: Richard
authors.initials: R
authors.lastname: Komorowski
authors.affiliation: Department of Biostatistics, Medical College of Wisconsin, Milwaukee, WI.
authors.forename: Daniel
authors.initials: D
authors.lastname: Eastwood
authors.affiliation: Department of Biostatistics, Medical College of Wisconsin, Milwaukee, WI.
authors.forename: Brent
authors.initials: B
authors.lastname: Logan
authors.affiliation: H. B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN.
authors.forename: Jie
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Immunology, Genentech, South San Francisco, CA.
authors.forename: Nico
authors.initials: N
authors.lastname: Ghilardi
authors.affiliation: Division of Autoimmunity and Inflammation, Merck Pharmaceuticals, Palo Alto, CA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Cua
authors.affiliation: Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI.
authors.forename: Calvin B
authors.initials: CB
authors.lastname: Williams
authors.affiliation: deDuve Institute, Université Catholique de Louvain, Brussels, Belgium; and.
authors.forename: Melanie
authors.initials: M
authors.lastname: Gaignage
authors.affiliation: Ludwig Cancer Institute, Brussels Branch, Brussels, Belgium.
authors.forename: Reece
authors.initials: R
authors.lastname: Marillier
authors.affiliation: Ludwig Cancer Institute, Brussels Branch, Brussels, Belgium.
authors.forename: Jacques
authors.initials: J
authors.lastname: van Snick
authors.affiliation: Department of Medicine.
authors.forename: William R
authors.initials: WR
authors.lastname: Drobyski
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D004195:Disease Models, Animal; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology*; D005786:Gene Expression Regulation / Q000276:immunology*; D006086:Graft vs Host Disease / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology; D018664:Interleukin-12 / Q000235:genetics / Q000276:immunology; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology; D007378:Interleukins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C556062:IL10 protein, mouse; C486767:Il27 protein, mouse; D015850:Interleukin-6; D007378:Interleukins; C577686:interleukin-6, mouse; D016753:Interleukin-10; D018664:Interleukin-12