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Synergistic Effect on the Attenuation of Collagen Induced Arthritis in Tumor Necrosis Factor Receptor I (TNFRI) and Interleukin 6 Double Knockout Mice
NORIHIKO YAMAGUCHI, SHIRO OHSHIMA, MITSUKO UMESHITA-SASAI, KATSUHIRO NISHIOKA, HIDEYUKI KOBAYASHI, TORU MIMA, TADAMITSU KISHIMOTO, and YUKIHIKO SAEKI
ABSTRACT.
Methods. CIA was induced in wild-type (Wt), TNFRI knockout (TNFRIKO), IL-6 knockout (IL-6KO), and DKO mice. Comparative studies were performed among these different mouse genotypes observing clinical (incidence, arthritis score), histological, radiologic, and immunological aspects. Results. More than 90% of the Wt, TNFRIKO, and IL-6KO mice developed definite CIA, while only 20% of the DKO mice did so. Severity of arthritis, indicated by the arthritis score, was significantly reduced in both the TNFRIKO and IL-6KO mice compared with the Wt mice. Moreover, the severity of arthritis in the DKO mice was significantly reduced compared with each single KO mouse (by arthritis scores; DKO vs TNFRIKO, IL-6KO mice, p < 0.05). In addition, histological and radiologic changes were also significantly reduced in the DKO mice compared with each single KO mouse (by histological and radiologic scores; DKO vs TNFRIKO, IL-6KO mice, p < 0.05 and p < 0.01 respectively). In immunological studies, serum anti-type II collagen (anti-CII) antibody concentrations were significantly decreased in the DKO mice compared with each single KO mouse (DKO vs TNFRIKO, IL-6KO mice, p < 0.01). Conclusion. Simultaneous blockade of TNFRI and IL-6 showed synergistic rather than additive effects on the attenuation of CIA. Combinations of anti-TNF-a and anti-IL-6 therapy may provide clinical benefits for treatment of rheumatoid arthritis compared with therapy against each single cytokine. (J Rheumatol 2003;30:22-7) Key Indexing Terms:
TUMOR NECROSIS FACTOR RECEPTOR I
From the Department of Molecular Medicine, Osaka University Medical School, Osaka; Tokyo Research Laboratories, Kowa Co. Ltd., Tokyo; and Osaka University, Osaka, Japan. Supported in part by grants from the Ministry of Education, Science and Culture, and the Ministry of Health and Welfare of Japan, and Kowa Pharmaceutical Company. N. Yamaguchi, MD; S. Ohshima, MD; M. Umeshita-Sasai, MD; K. Nishioka, MD, Department of Molecular Medicine, Osaka University Medical School; H. Kobayashi, BS, Tokyo Research Laboratories, Kowa Co. Ltd.; T. Mima, MD, Department of Molecular Medicine, Osaka University Medical School; T. Kishimoto, MD, Osaka University; Y. Saeki, MD, Department of Molecular Medicine, Osaka University Medical School. Address reprint requests to Dr. Y. Saeki, Department of Molecular Medicine, Osaka University Medical School, 2-2 Yamada-oka, Suita City, Osaka 565-0871, Japan. E-mail: saekiy@imed3.med.osaka-u.ac.jp Submitted July 4, 2001; revision accepted July 3, 2002. |