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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

Keon-Il Im, Nayoun Kim, Jung-Yeon Lim, Young-Sun Nam, Eun-Sol Lee, Eun-Jung Kim, Hyoung Jin Kim, Soon Ha Kim and Seok-Goo Cho
J Immunol June 1, 2015, 194 (11) 5223-5232; DOI: https://doi.org/10.4049/jimmunol.1402609
Keon-Il 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;
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Nayoun 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;
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Jung-Yeon 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;
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Young-Sun 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;
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Eun-Sol Lee
*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;
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Eun-Jung Kim
†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;
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Hyoung Jin Kim
‡Strategy and Development, LG Life Sciences Ltd., Seoul 2305-738, Korea; and
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Soon Ha Kim
‡Strategy and Development, LG Life Sciences Ltd., Seoul 2305-738, Korea; and
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Seok-Goo Cho
*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
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Abstract

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.

Footnotes

  • This work was supported by Grant HI14C3417 from the Korea Healthcare Technology Research and Development Project, Ministry for Health, Welfare, and Family Affairs, Republic of Korea.

  • The online version of this article contains supplemental material.

  • Abbreviations used in this article:

    BMT
    bone marrow transplantation
    DAMP
    damage-associated molecular pattern
    DC
    dendritic cell
    GVHD
    graft-versus-host disease
    HMGB1
    high-mobility group box 1
    HSCT
    hematopoietic stem cell transplantation
    NecroX
    cyclopentylamino carboxymethylthiazolylindole
    PKC
    protein kinase C
    RAGE
    receptor for advanced glycation end products
    ROS
    reactive oxygen species
    Treg
    regulatory T cell.

  • Received October 16, 2014.
  • Accepted March 27, 2015.
  • Copyright © 2015 by The American Association of Immunologists, Inc.

This article is distributed under The American Association of Immunologists, Inc., Reuse Terms and Conditions for Author Choice articles.

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The Journal of Immunology: 194 (11)
The Journal of Immunology
Vol. 194, Issue 11
1 Jun 2015
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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
Keon-Il Im, Nayoun Kim, Jung-Yeon Lim, Young-Sun Nam, Eun-Sol Lee, Eun-Jung Kim, Hyoung Jin Kim, Soon Ha Kim, Seok-Goo Cho
The Journal of Immunology June 1, 2015, 194 (11) 5223-5232; DOI: 10.4049/jimmunol.1402609

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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
Keon-Il Im, Nayoun Kim, Jung-Yeon Lim, Young-Sun Nam, Eun-Sol Lee, Eun-Jung Kim, Hyoung Jin Kim, Soon Ha Kim, Seok-Goo Cho
The Journal of Immunology June 1, 2015, 194 (11) 5223-5232; DOI: 10.4049/jimmunol.1402609
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