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Anti-Interleukin 6 Receptor Antibody Inhibits Murine AA-Amyloidosis
MASAHIKO MIHARA, MASASHI SHIINA, NORIHIRO NISHIMOTO, KAZUYUKI YOSHIZAKI, TADAMITSU KISHIMOTO, and KEN-ICHI AKAMATSU
ABSTRACT. Methods. A transient model was induced by the injection of amyloid enhancing factor (AEF) and adjuvant treatment in C57BL/6 mice. Monoclonal IgG1 antibody, MR16-1, was injected intraperitoneally just once before the injection of AEF and adjuvant. After 2 and 5 weeks, mice were sacrificed and histologically examined. In contrast, a chronic model was induced by AEF injection into IL-6 transgenic mice. One week later, in order to avoid neutralizing antibody production, MR16-1 (200 mg/kg) was injected intravenously. MR16-1 (5 mg/kg) was injected subcutaneously twice a week from the next week. Three and 6 weeks after AEF injection, mice were sacrificed and histologically examined.
Results. In the transient model, amyloid deposition was observed in the spleen, liver, and kidney as early as 2 weeks after treatment. MR16-1 completely prevented amyloid deposition. Although IL-6 production was not suppressed, SAA production was significantly suppressed. In the chronic model, substantial amyloid deposition was seen in multiple organs and tissues as well as the spleen, liver, and kidney. MR16-1 suppressed amyloid deposition in many organs, even when injected one week after AEF injection; it showed a tendency to decrease SAA and IL-6 levels were decreased.
Conclusion. IL-6 is a key cytokine for the induction of AA-amyloidosis, and anti-IL-6R therapy appears promising for the treatment of AA-amyloidosis. (J Rheumatol 2004;31:1132-8) Key Indexing Terms:
ANTI-INTERLEUKIN 6 RECEPTOR
From Fuji-Gotemba Research Laboratories, Chugai Pharmaceutical Co. Ltd, Shizuoka; Graduate School of Frontier Biosciences, and Department of Medical Science I, School of Health and Sport Sciences, Osaka University, Osaka, Japan. M. Mihara, PhD; M. Shiina, MS, Fuji-Gotemba Research Laboratories, Chugai Pharmaceutical Co. Ltd.; N. Nishimoto, MD, Graduate School of Frontier Biosciences, Osaka University; K. Yoshizaki, MD, Department of Medical Science I, School of Health and Sport Sciences, Osaka University; T. Kishimoto, MD, Osaka University; K. Akamatsu, PhD, Fuji-Gotemba Research Laboratories, Chugai Pharmaceutical Co. Ltd. Address reprint requests to Dr. M. Mihara, Fuji-Gotemba Research Laboratories, Chugai Pharmaceutical Co. Ltd., 135, Komakado 1-chome, Gotemba-shi, Shizuoka, 412-8513, Japan. E-mail: miharamsh@chugai-pharm.co.jp Submitted March 25, 2003; revision accepted December 19, 2003.
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