Faculty Collaboration Database

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

Date

06/06/2009

Pubmed ID

19491393

Pubmed Central ID

PMC2716024

DOI

10.1182/blood-2009-01-197178

Scopus ID

2-s2.0-68249160054 (requires institutional sign-in at Scopus site)   246 Citations

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.

Author List

Chen X, Das R, Komorowski R, Beres A, Hessner MJ, Mihara M, Drobyski WR

Authors

Xiao Chen MD, PhD Associate Professor in the Medicine department at Medical College of Wisconsin
William R. Drobyski MD Professor in the Medicine department at Medical College of Wisconsin
Martin J. Hessner PhD Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Antibodies
Bone Marrow Transplantation
Cell Proliferation
Cells, Cultured
Graft vs Host Disease
Interleukin-6
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Knockout
Receptors, Interleukin-6
Severity of Illness Index
Signal Transduction
T-Lymphocytes, Regulatory
Transplantation Conditioning