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
06/06/2009Pubmed ID
19491393Pubmed Central ID
PMC2716024DOI
10.1182/blood-2009-01-197178Scopus ID
2-s2.0-68249160054 (requires institutional sign-in at Scopus site) 246 CitationsAbstract
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 WRAuthors
Xiao Chen MD, PhD Associate Professor in the Medicine department at Medical College of WisconsinWilliam 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
AnimalsAntibodies
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