The Free Radical Scavenger NecroX-7 Attenuates Acute Graft-versus-Host Disease via Reciprocal Regulation of Th1/Regulatory T Cells and Inhibition of HMGB1 Release.
Graft-versus-host disease (GVHD) is a major complication associated with allogeneic hematopoietic stem cell transplantation. Despite the prominent role of the adaptive immune system, the importance of controlling the innate immune system in the pathogenesis of GVHD has recently been rediscovered. High-mobility group box 1 (HMGB1) is a crucial damage-associated molecular pattern signal that functions as a potent innate immune mediator in GVHD. In the present study, we investigated treatment of experimental GVHD through HMGB1 blockade using the compound cyclopentylamino carboxymethylthiazolylindole (NecroX)-7. Treated animals significantly attenuated GVHD-related mortality and inhibited severe tissue damage. These protective effects correlated with the decrease in HMGB1 expression and lower levels of reactive oxidative stress. Additionally, NecroX-7 inhibited the HMGB1-induced release of TNF and IL-6, as well as the expression of TLR-4 and receptor for advanced glycation end products. We also observed increased regulatory T cell numbers, which may be associated with regulation of differentiation signals independent of HMGB1. Taken together, these data indicate that NecroX-7 protects mice against lethal GVHD by reciprocal regulation of regulatory T/Th1 cells, attenuating systemic HMGB1 accumulation and inhibiting HMGB1-mediated inflammatory response. Our results indicate the possibility of a new use for a clinical drug that is effective for the treatment of GVHD.
Institute for Translational Research and Molecular Imaging, Catholic Research Institute of Medical Science, Catholic University of Korea, Seoul 137-701, Korea; Laboratory of Immune Regulation, Convergent Research Consortium for Immunologic Disease, Catholic University of Korea College of Medicine, St. Mary's Hospital, Seoul 137-701, Korea;
Keon-Il
KI
Im
Institute for Translational Research and Molecular Imaging, Catholic Research Institute of Medical Science, Catholic University of Korea, Seoul 137-701, Korea; Laboratory of Immune Regulation, Convergent Research Consortium for Immunologic Disease, Catholic University of Korea College of Medicine, St. Mary's Hospital, Seoul 137-701, Korea;
Nayoun
N
Kim
Institute for Translational Research and Molecular Imaging, Catholic Research Institute of Medical Science, Catholic University of Korea, Seoul 137-701, Korea; Laboratory of Immune Regulation, Convergent Research Consortium for Immunologic Disease, Catholic University of Korea College of Medicine, St. Mary's Hospital, Seoul 137-701, Korea;
Jung-Yeon
JY
Lim
Institute for Translational Research and Molecular Imaging, Catholic Research Institute of Medical Science, Catholic University of Korea, Seoul 137-701, Korea; Laboratory of Immune Regulation, Convergent Research Consortium for Immunologic Disease, Catholic University of Korea College of Medicine, St. Mary's Hospital, Seoul 137-701, Korea;
Young-Sun
YS
Nam
Institute for Translational Research and Molecular Imaging, Catholic Research Institute of Medical Science, Catholic University of Korea, Seoul 137-701, Korea; Laboratory of Immune Regulation, Convergent Research Consortium for Immunologic Disease, Catholic University of Korea College of Medicine, St. Mary's Hospital, Seoul 137-701, Korea;
Eun-Sol
ES
Lee
Laboratory of Immune Regulation, Convergent Research Consortium for Immunologic Disease, Catholic University of Korea College of Medicine, St. Mary's Hospital, Seoul 137-701, Korea;
Eun-Jung
EJ
Kim
Strategy and Development, LG Life Sciences Ltd., Seoul 2305-738, Korea; and.
Hyoung Jin
HJ
Kim
Strategy and Development, LG Life Sciences Ltd., Seoul 2305-738, Korea; and.
Soon Ha
SH
Kim
Institute for Translational Research and Molecular Imaging, Catholic Research Institute of Medical Science, Catholic University of Korea, Seoul 137-701, Korea; Laboratory of Immune Regulation, Convergent Research Consortium for Immunologic Disease, Catholic University of Korea College of Medicine, St. Mary's Hospital, Seoul 137-701, Korea; Department of Hematology, Catholic Blood and Marrow Transplantation Center, Seoul St. Mary's Hospital, Catholic University of Korea College of Medicine, Seoul 137-701, Korea chosg@catholic.ac.kr.
Seok-Goo
SG
Cho
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation; D005260:Female; D016166:Free Radical Scavengers / Q000627:therapeutic use*; D006086:Graft vs Host Disease / Q000188:drug therapy* / Q000276:immunology; D024243:HMGB1 Protein / Q000378:metabolism*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D009930:Organic Chemicals / Q000627:therapeutic use*; D018384:Oxidative Stress / Q000187:drug effects; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000096:biosynthesis; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000096:biosynthesis; D014184:Transplantation, Homologous; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D016166:Free Radical Scavengers; D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; D015850:Interleukin-6; D009930:Organic Chemicals; D017382:Reactive Oxygen Species; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; C556282:necrox-7; D011493:Protein Kinase C