Interleukin-6 modulates graft-versus-host responses after experimental allogeneic bone marrow transplantation

Tawara, Isao, Koyama, Motoko, Liu, Chen, Toubai, Tomomi, Thomas, Dafydd, Evers, Rebecca, Chockley, Peter, Nieves, Evelyn, Sun, Yaping, Lowler, Kathleen P., Malter, Chelsea, Nishimoto, Norihiro, Hill, Geoffrey R. and Reddy, Pavan (2011) Interleukin-6 modulates graft-versus-host responses after experimental allogeneic bone marrow transplantation. Clinical Cancer Research, 17 1: 77-88. doi:10.1158/1078-0432.CCR-10-1198


Author Tawara, Isao
Koyama, Motoko
Liu, Chen
Toubai, Tomomi
Thomas, Dafydd
Evers, Rebecca
Chockley, Peter
Nieves, Evelyn
Sun, Yaping
Lowler, Kathleen P.
Malter, Chelsea
Nishimoto, Norihiro
Hill, Geoffrey R.
Reddy, Pavan
Title Interleukin-6 modulates graft-versus-host responses after experimental allogeneic bone marrow transplantation
Journal name Clinical Cancer Research   Check publisher's open access policy
ISSN 1078-0432
1557-3265
Publication date 2011-01-01
Year available 2011
Sub-type Article (original research)
DOI 10.1158/1078-0432.CCR-10-1198
Open Access Status Not yet assessed
Volume 17
Issue 1
Start page 77
End page 88
Total pages 12
Place of publication Philadelphia, PA United States
Publisher American Association for Cancer Research
Language eng
Abstract Purpose: 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.
Formatted abstract
Purpose: 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.

Experimental Design: 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.

Conclusion: 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.
Keyword Regulatory T-Cells
Antigen-Presenting Cells
Necrosis-Factor-Alpha
Acute Gvhd
Rheumatoid-Arthritis
Leukemia Responses
Epithelial-Cells
Serum Levels
Disease
Cancer
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID AI-075284
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: School of Medicine Publications
UQ Diamantina Institute Publications
 
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