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.
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