Blockade of interleukin-6 signaling augments regulatory T-cell reconstitution and attenuates the severity of graft-versus-host disease.
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.
Chen
Xiao
X
Bone Marrow Transplant Program, and Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Das
Rupali
R
Komorowski
Richard
R
Beres
Amy
A
Hessner
Martin J
MJ
Mihara
Masahiko
M
Drobyski
William R
WR
D000818:Animals; D000906:Antibodies / Q000494:pharmacology* / Q000627:therapeutic use; D016026:Bone Marrow Transplantation / Q000276:immunology / Q000379:methods; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D006086:Graft vs Host Disease / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019947:Receptors, Interleukin-6 / Q000037:antagonists & inhibitors / Q000378:metabolism; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D019172:Transplantation Conditioning / Q000379:methods; D000093242:Interleukin-6 Inhibitors
D000906:Antibodies; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D000093242:Interleukin-6 Inhibitors