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Blockade of interleukin-27 signaling reduces GVHD in mice by augmenting Treg reconstitution and stabilizing Foxp3 expression.
Belle, Ludovic; Agle, Kimberle; Zhou, Vivian; Yin-Yuan, Cheng; Komorowski, Richard; Eastwood, Daniel; Logan, Brent; Sun, Jie; Ghilardi, Nico; Cua, Daniel; Williams, Calvin B; Gaignage, Melanie; Marillier, Reece; van Snick, Jacques; Drobyski, William R.
Afiliación
  • Belle L; Department of Medicine.
  • Agle K; Department of Medicine.
  • Zhou V; Department of Medicine.
  • Yin-Yuan C; Department of Medicine.
  • Komorowski R; Department of Pathology, and.
  • Eastwood D; Department of Biostatistics, Medical College of Wisconsin, Milwaukee, WI.
  • Logan B; Department of Biostatistics, Medical College of Wisconsin, Milwaukee, WI.
  • Sun J; H. B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN.
  • Ghilardi N; Department of Immunology, Genentech, South San Francisco, CA.
  • Cua D; Division of Autoimmunity and Inflammation, Merck Pharmaceuticals, Palo Alto, CA.
  • Williams CB; Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI.
  • Gaignage M; deDuve Institute, Université Catholique de Louvain, Brussels, Belgium; and.
  • Marillier R; Ludwig Cancer Institute, Brussels Branch, Brussels, Belgium.
  • van Snick J; Ludwig Cancer Institute, Brussels Branch, Brussels, Belgium.
  • Drobyski WR; Department of Medicine.
Blood ; 128(16): 2068-2082, 2016 10 20.
Article en En | MEDLINE | ID: mdl-27488350
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Transducción de Señal / Regulación de la Expresión Génica / Interleucinas / Linfocitos T Reguladores / Factores de Transcripción Forkhead / Enfermedad Injerto contra Huésped Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Blood Año: 2016 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Transducción de Señal / Regulación de la Expresión Génica / Interleucinas / Linfocitos T Reguladores / Factores de Transcripción Forkhead / Enfermedad Injerto contra Huésped Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Blood Año: 2016 Tipo del documento: Article Pais de publicación: Estados Unidos