Blockade of interleukin-6 signaling augments regulatory T-cell reconstitution and attenuates the severity of graft-versus-host disease

X Chen, R Das, R Komorowski, A Beres… - Blood, The Journal …, 2009 - ashpublications.org
X Chen, R Das, R Komorowski, A Beres, MJ Hessner, M Mihara, WR Drobyski
Blood, The Journal of the American Society of Hematology, 2009ashpublications.org
Graft-versus-host disease (GVHD) is the major complication after allogeneic bone marrow
transplantation and is characterized by the overproduction of proinflammatory cytokines. In
this study, we have identified interleukin-6 (IL-6) as a critical inflammatory cytokine that alters
the balance between the effector and regulatory arms of the immune system and drives a
proinflammatory phenotype that is a defining characteristic of GVHD. Our results
demonstrate that inhibition of the IL-6 signaling pathway by way of antibody-mediated …
Abstract
Graft-versus-host disease (GVHD) is the major complication after allogeneic bone marrow transplantation and is characterized by the overproduction of proinflammatory cytokines. In this study, we have identified interleukin-6 (IL-6) as a critical inflammatory cytokine that alters the balance between the effector and regulatory arms of the immune system and drives a proinflammatory phenotype that is a defining characteristic of GVHD. Our results demonstrate that inhibition of the IL-6 signaling pathway by way of antibody-mediated blockade of the IL-6 receptor (IL-6R) markedly reduces pathologic damage attributable to GVHD. This is accompanied by a significant increase in the absolute number of regulatory T cells (Tregs) that is due to augmentation of thymic-dependent and thymic-independent Treg production. Correspondingly, there is a significant reduction in the number of T helper 1 and T helper 17 cells in GVHD target organs, demonstrating that blockade of IL-6 signaling decreases the ratio of proinflammatory T cells to Tregs. These studies demonstrate that antibody blockade of the IL-6R serves to recalibrate the effector and regulatory arms of the immune system and represents a novel, potentially clinically translatable, strategy for the attenuation of GVHD.
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