Interleukin-6 modulates graft-versus-host responses after experimental allogeneic bone marrow transplantation.
OBJECTIVE
The graft-versus-tumor (GVT) effect is a potent form of immunotherapy against many hematologic malignancies and some solid tumors. The beneficial GVT effect after allogeneic bone marrow transplantation (BMT) is tightly linked to its most significant complication, graft-versus-host disease (GVHD). The role of interleukin-6 (IL-6) after allogeneic BMT is not well understood. This study used a series of complementary knockout and antibody blockade strategies to analyze the impact of IL-6 in multiple clinically relevant murine models of GVHD and GVT.


METHODS
We examined the effect of the source of IL-6 by analyzing the role IL-6 deficiency in donor T cells, donor bone marrow or in host tissues. We confirmed and extended the relevance of IL-6 deficiency on GVHD and GVT by treating BMT recipients with anti-mouse IL-6 receptor (IL-6R), MR16-1.


RESULTS
Deficiency of IL-6 in donor T cells led to prolongation of survival. Total inhibition of IL-6 with MR16-1 caused an even greater reduction in GVHD-induced mortality. The reduction in GVHD was independent of the direct effects on T effector cell expansion or donor regulatory T cells. GVT responses were preserved after treatment with MR16-1.


CONCLUSIONS
MR16-1 treatment reduced GVHD and preserved sufficient GVT. Tocilizumab, a humanized anti-IL-6R monoclonal antibody (mAb), is approved in several countries including the United States and European Union for the treatment of rheumatoid arthritis and other inflammatory diseases. Blockade of IL-6 with anti-IL-6R mAb therapy may be testable in clinical trials as an adjunct to prevent GVHD in BMT patients without a significant loss of GVT.
Department of Internal Medicine and University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan 48109-0942, USA.
Isao
I
Tawara
Motoko
M
Koyama
Chen
C
Liu
Tomomi
T
Toubai
Dafydd
D
Thomas
Rebecca
R
Evers
Peter
P
Chockley
Evelyn
E
Nieves
Yaping
Y
Sun
Kathleen P
KP
Lowler
Chelsea
C
Malter
Norihiro
N
Nishimoto
Geoffrey R
GR
Hill
Pavan
P
Reddy
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D016026:Bone Marrow Transplantation / Q000276:immunology*; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology* / Q000628:therapy; D015850:Interleukin-6 / Q000172:deficiency / Q000276:immunology*; D051379:Mice; D057507:Mice, 129 Strain; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D014184:Transplantation, Homologous; D000093242:Interleukin-6 Inhibitors
D000911:Antibodies, Monoclonal; D015850:Interleukin-6; D000093242:Interleukin-6 Inhibitors