IL-6 blockade attenuates the development of murine sclerodermatous chronic graft-versus-host disease.
Systemic sclerosis (scleroderma) is a connective tissue disease characterized by excessive extracellular matrix deposition in the skin and visceral organs. Serum IL-6 levels are reported to be elevated in human scleroderma and chronic graft-versus-host disease (cGVHD) patients. IL-6 blockade using anti-IL-6 receptor mAb (anti-IL-6R mAb) results in amelioration of the pathologic symptoms of some autoimmune diseases such as rheumatoid arthritis and juvenile idiopathic arthritis. In this study, we examined the effects of anti-IL-6R mAb on either prevention or treatment of murine sclerodermatous cGVHD (Scl-cGVHD). We found that serum IL-6 levels in Scl-cGVHD mice gradually increased after bone marrow transplantation. Administration of anti-IL-6R mAb attenuated the development of severe Scl-cGVHD and fibrosis and resulted in an increase in CD4(+)CD25(+)FoxP3(+) regulatory T cells. However, treatment of established Scl-cGVHD with anti-IL-6R mAb showed no effects on disease severity. The effects of anti-IL-6R mAb were mostly inhibited by anti-CD25 mAb. Together, our results indicate that IL-6 has an important role in the pathogenesis of Scl-cGVHD. IL-6 blockade may be an effective approach for preventing Scl-cGVHD and treating cGVHD and scleroderma in humans.
Department of Dermatology, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan.
Doanh
D
Le Huu
Takashi
T
Matsushita
Guihua
G
Jin
Yasuhito
Y
Hamaguchi
Minoru
M
Hasegawa
Kazuhiko
K
Takehara
Manabu
M
Fujimoto
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000918:Antibody Specificity / Q000276:immunology; D016026:Bone Marrow Transplantation / Q000009:adverse effects* / Q000276:immunology; D002908:Chronic Disease; D004195:Disease Models, Animal; D005260:Female; D006086:Graft vs Host Disease / Q000209:etiology / Q000276:immunology / Q000517:prevention & control; D053645:Interleukin-2 Receptor alpha Subunit / Q000037:antagonists & inhibitors / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D019947:Receptors, Interleukin-6 / Q000037:antagonists & inhibitors / Q000276:immunology; D012595:Scleroderma, Systemic / Q000150:complications / Q000188:drug therapy / Q000276:immunology; D012720:Severity of Illness Index; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology; D000093242:Interleukin-6 Inhibitors
D000911:Antibodies, Monoclonal; D053645:Interleukin-2 Receptor alpha Subunit; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D000093242:Interleukin-6 Inhibitors; C508018:Il2ra protein, mouse