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

Blood. 2009 Jul 23;114(4):891-900. doi: 10.1182/blood-2009-01-197178. Epub 2009 Jun 2.


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.

Publication types

  • Evaluation Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies / pharmacology*
  • Antibodies / therapeutic use
  • Bone Marrow Transplantation / immunology
  • Bone Marrow Transplantation / methods
  • Cell Proliferation / drug effects*
  • Cells, Cultured
  • Graft vs Host Disease / immunology
  • Graft vs Host Disease / metabolism
  • Graft vs Host Disease / prevention & control*
  • Interleukin-6 / antagonists & inhibitors*
  • Interleukin-6 / genetics
  • Interleukin-6 / immunology
  • Interleukin-6 / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptors, Interleukin-6 / antagonists & inhibitors
  • Receptors, Interleukin-6 / metabolism
  • Severity of Illness Index
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • T-Lymphocytes, Regulatory / drug effects*
  • T-Lymphocytes, Regulatory / metabolism
  • T-Lymphocytes, Regulatory / physiology
  • Transplantation Conditioning / methods


  • Antibodies
  • Interleukin-6
  • Receptors, Interleukin-6