Table 2 | Experimental
disease models responding to therapy targeting HMGB1
Model
HMGB1 antagonist (reference)
Result
Arthritis
Anti-HMGB1 antibodies (S41–S44)
Reduced inflammation and tissue
Recombinant HMGB1 A box (S41,S43)
destruction
Blockade of RAGE-signaling (S45)
Thrombomodulin (S46)
Neuropathic pain
Anti-HMGB1 antibodies (S47,S48)
Alleviation of pain.
Endotoxemia
Anti-HMGB1 antibodies (S49)
Protection from lethality.
Thrombomodulin (S50, S51)
Sepsis
Anti-HMGB1 antibodies (S49,S52)
Improved survival (even after
Recombinant HMGB1 A box (S53)
administration 24 h after onset of disease)
Blockade of RAGE-signaling (S54)
representing a uniquely wide therapeutic
window.
Pancreatitis
Anti-HMGB1 antibodies (S55)
Decreased severity of pancreatitis.
Recombinant HMGB1 A box (S56)
Colitis
Anti-HMGB1 antibodies (S57,S58)
Reduced inflammation and tumor
incidence
Hemorrhagic shock
Anti-HMGB1 antibodies (S59,S60)
Improved survival and reduced organ
dysfunction.
Stroke
Anti-HMGB1 antibodies (S61,S62)
Marked neuroprotection and reduced
Recombinant HMGB1 A box (S62)
magnitude of cell death.
Epilepsy
Recombinant HMGB1 A box (S63)
Anticonvulsant effects.
Ischemia-
Anti-HMGB1 antibodies (S64)
Attenuation of shock and tissue damage
reperfusion injury
Recombinant HMGB1 A box (S65)
and reduced cytokine release.
Atherosclerosis
Anti-HMGB1 antibodies (S66)
Prevention of disease development
Myocardial
Anti-HMGB1 antibodies (S67)
Increased infarcts.
Recombinant HMGB1 A box (S65)
Attenuation of tissue damage.
Anti-HMGB1 antibodies (S68)
Enhances allograft survival.
Recombinant HMGB1 A box (S69)
Enhances allograft survival.
Respiratory
Anti-HMGB1 antibodies (S70–S72)
Reduced inflammation and development
disorders
Recombinant HMGB1 A box (S73)
of pulmonary fibrosis.
Acetaminophen-
Anti-HMGB1 antibodies (S74)
Improved survival.
infarction
Transplantation
induced liver
Reduced hepatotoxicity.
damage
Abbreviation: RAGE, receptor for advanced glycation end products.
S41.
Kokkola, R. et al. Successful treatment of collagen-induced arthritis in mice
and rats by targeting extracellular high mobility group box chromosomal protein 1
activity. Arthritis Rheum. 48, 2052–2058 (2003).
S42.
Hamada, T. et al. Extracellular high mobility group box chromosomal protein
1 is a coupling factor for hypoxia and inflammation in arthritis. Arthritis Rheum. 58,
2675–2685 (2008).
S43.
Östberg, T. et al. Protective targeting of high mobility group box chromosomal
protein 1 in a spontaneous arthritis model. Arthritis Rheum. 62, 2963–2972 (2010).
S44.
Schierbeck, H. et al. Monoclonal anti-HMGB1.antibody protection in two
experimental arthritis models. Mol. Med. 17, 1039–1044 (2011).
1
S45.
Hofmann, M. A. et al. RAGE and arthritis: the G82S polymorphism amplifies
the inflammatory response. Genes Immun. 3, 123–135 (2002).
S46.
Van de Wouwer, M. et al. The lectin-like domain of thrombomodulin interferes
with complement activation and protects against arthritis. J. Thromb. Haemost. 4, 1813–
1824 (2006).
S47.
Otoshi, K., Kikuchi, S., Kato, K., Sekiguchi, M., Konno, S. Anti-HMGB1
neutralization antibody improves pain-related behavior induced by application of
autologous nucleus pulposus onto nerve roots in rats. Spine (Phila Pa 1976) 36,
E692-E698 (2011).
S48.
Shibasaki, M. et al. Induction of high mobility group box-1 in dorsal root
ganglion contributes to pain hypersensitivity after peripheral nerve injury. Pain 149,
514–521 (2010).
S49.
Wang, H. et al. HMG-1 as a late mediator of endotoxin lethality in mice.
Science 285, 248–251 (1999).
S50.
Abeyama, K. et al. The N-terminal domain of thrombomodulin sequesters
high-mobility group-B1 protein, a novel antiinflammatory mechanism. J. Clin. Investig.
115, 1267–1274 (2005).
S51.
Nagato, M., Okamoto, K., Abe, Y., Higure, A., Yamaguchi, K. Recombinant
human soluble thrombomodulin decreases the plasma high-mobility group box-1 protein
levels, whereas improving the acute liver injury and survival rates in experimental
endotoxemia. Crit. Care. Med. 37, 2181–2186 (2009).
S52.
Qin, S. et al. Role of HMGB1 in apoptosis-mediated sepsis lethality. J. Exp. Med.
203, 1637–1642 (2006).
S53.
Yang, H. et al. Reversing established sepsis with antagonists of endogenous high-
mobility group Box 1. Proc. Natl. Acad. Sci. USA 101, 296–301 (2004).
S54.
Lutterloh, E. C. et al. Inhibition of the RAGE products increases survival in
experimental models of severe sepsis and systemic infection. Crit. Care 11, R122 (2007).
S55.
Sawa, H. et al. Blockade of high mobility group box-1 protein attenuates
experimental severe acute pancreatitis. World J. Gastroenterol. 12, 7666–7670 (2006).
S56.
Yuan, H. et al. Protective effect of HMGB1 A box on organ injury of acute
pancreatitis in mice. Pancreas 38, 143–48 (2009).
S57.
Maeda, S. et al. Essential roles of high-mobility group Box 1 in the
development of murine colitis and colitis-associated cancer. Biochem. Biophys. Res.
Commun. 360, 394–400 (2007).
Yang, R. et al. Bile high-mobility group Box 1 contributes to gut barrier
S58.
dysfunction in experimental endotoxemia. Am. J. Physiol. Regul. Integr. Comp. Physiol.
297, R362–R369(2009).
S59.
Yang, R. et al. Anti-HMGB1 neutralizing antibody ameliorates gut barrier
dysfunction and improves survival after hemorrhagic shock. Mol. Med. 12, 105–114
(2006).
S60.
Kim, J. Y. et al. HMGB1 contributes to the development of acute lung injury
after hemorrhage. Am. J. Physiol. Lung Cell Mol. Physiol. 288, L958-L965 (2005).
S61.
Liu, K. et al. Anti-high mobility group Box 1 monoclonal antibody ameliorates
brain infarction induced by transient ischemia in rats. FASEB J. 21, 3904–3916 (2007).
S62.
Muhammad, S. et al. The HMGB1 receptor RAGE mediates ischemic brain
damage. J. Neurosci. 28, 12023–12031 (2008).
S63.
Maroso M. et al. Toll-like receptor 4 and high-mobility group box-1 are
involved in ictogenesis and can be targeted to reduce seizures. Nat. Med. 16, 413–419
(2010).
2
S64.
Tsung, A. et al. The nuclear factor HMGB1 mediates hepatic injury after
murine liver ischemia-reperfusion. J. Exp. Med. 201, 1135–1143 (2005).
S65.
Andrassy, M. et al. High-mobility group box-1 in ischemia-reperfusion injury
of the heart. Circulation 117, 3216–3226 (2008).
S66.
Kanellakis, P. et al. High-mobility group box protein 1 neutralization reduces
development of diet-induced atherosclerosis in apolipoprotein e-deficient mice.
Arterioscler. Thromb. Vasc. Biol. 31, 313–319 (2011).
S67.
Oozawa, S. et al. Effects of HMGB1 on ischemia-reperfusion injury in the rat
heart. Circ. J. 72, 1178–1184 (2008).
S68.
Gao, Q. et al. TLR4 mediates early graft failure after intraportal islet
transplantation. Am. J. Transplant. 10, 1588–1596 (2010).
S69.
Huang Y. et al. Extracellular HMGB1 functions as an innate immune-mediator
implicated in murine cardiac allograft acute rejection. Am. J. Transplant. 7, 799–808
(2007).
S70.
Abraham, E., Arcaroli, J., Carmody, A., Wang, H., Tracey, K. J. HMG-1 as a
mediator of acute lung inflammation. J. Immunol. 165, 2950–2954 (2000).
S71.
Ogawa, E. N. et al. Contribution of high-mobility group box-1 to the
development of ventilator-induced lung injury. Am. J. Respir. Crit. Care Med. 174, 400–
407 (2006).
S72.
Ueno, H. et al. Contributions of high mobility group box protein in
experimental and clinical acute lung injury. Am. J. Respir. Crit. Care Med. 170, 1310–
1316 (2004).
S73.
Gong, Q. et al. Protective effect of antagonist of high-mobility group Box 1 on
lipopolysaccharide-induced acute lung injury in mice. Scand. J. Immunol. 69, 29–35
(2009).
S74.
Antoine, D. J., Williams, D. P., Kipar, A., Laverty, H., Park, B. K. Diet
restriction inhibits apoptosis and HMGB1 oxidation and promotes inflammatory cell
recruitment during acetaminophen hepatotoxicity. Mol. Med. 16, 479–490 (2010).
3