TY - JOUR
T1 - Blockade of interleukin-27 signaling reduces GVHD in mice by augmenting Treg reconstitution and stabilizing Foxp3 expression
AU - Belle, Ludovic
AU - Agle, Kimberle
AU - Zhou, Vivian
AU - Yin-Yuan, Cheng
AU - Komorowski, Richard
AU - Eastwood, Daniel
AU - Logan, Brent
AU - Sun, Jie
AU - Ghilardi, Nico
AU - Cua, Daniel
AU - Williams, Calvin B.
AU - Gaignage, Melanie
AU - Marillier, Reece
AU - Van Snick, Jacques
AU - Drobyski, William R.
N1 - Funding Information:
This work was supported by grants from the National Institutes of Health National Heart, Lung, and Blood Institute (HL064603 and HL126166) and by awards from the Midwest Athletes Against Childhood Cancer Fund (W.R.D.). L.B. was supported by a grant from Wallonia Brussels International.
Publisher Copyright:
© 2016 by The American Society of Hematology.
Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.
PY - 2016/10/20
Y1 - 2016/10/20
N2 - 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.
AB - 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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U2 - 10.1182/blood-2016-02-698241
DO - 10.1182/blood-2016-02-698241
M3 - Article
C2 - 27488350
AN - SCOPUS:84992051377
VL - 128
SP - 2068
EP - 2082
JO - Blood
JF - Blood
SN - 0006-4971
IS - 16
ER -