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Blood, 15 November 2008, Vol. 112, No. 10, pp. 3959-3964. Prepublished online as a Blood First Edition Paper on September 10, 2008; DOI 10.1182/blood-2008-05-155846. This Article Full Text (PDF) All Versions of this Article: blood-2008-05-155846v1 112/10/3959    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Nishimoto, N. Articles by Kakehi, T. Search for Related Content PubMed PubMed Citation Articles by Nishimoto, N. Articles by Kakehi, T. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted May 13, 2008 Accepted July 18, 2008 Mechanisms and pathological significances in increase in serum interleukin-6 (IL-6) and soluble IL-6 receptor after administration of an anti-IL-6 receptor antibody, tocilizumab, in patients with rheumatoid arthritis and Castleman's disease Norihiro Nishimoto*, Kimio Terao, Toru Mima, Hideko Nakahara, Nobuhiro Takagi, and Takahiro Kakehi Laboratory of Immune Regulation, Graduate School of Frontier Bioscience, Osaka University, Suita-city, Osaka, Japan Chugai Pharmaceutical Co.,Ltd, Tokyo, Japan Department of Internal Medicine, NTT West Osaka Hospital, Osaka, Japan * Corresponding author; email: norihiro{at}fbs.osaka-u.ac.jp. Interleukin-6 (IL-6) plays pathological roles in immune-inflammatory diseases such as rheumatoid arthritis (RA) and Castleman's disease. By inhibiting IL-6 receptors (IL-6R), tocilizumab (a humanized anti-IL-6R antibody) ameliorates the symptoms of these diseases and normalizes acute phase proteins, including CRP. We found that tocilizumab treatment increased serum levels of IL-6 and soluble IL-6R (sIL-6R). To investigate the pathological significance of these increases, we analyzed the kinetics of serum IL-6 and sIL-6R, and the proportion of sIL-6R saturated with tocilizumab, after tocilizumab administration in patients with RA and Castleman's disease and then compared the results with the CRP values. Serum IL-6 and sIL-6R markedly increased after tocilizumab administration in both RA and Castleman's disease. As long as free tocilizumab was detectable, sIL-6R was saturated with tocilizumab and IL-6 signaling was completely inhibited. We concluded that it is likely that sIL-6R increased because its elimination half-life was prolonged by the formation of tocilizumab/sIL-6R immune complex, and that free serum IL-6 increased because IL-6R-mediated consumption of IL-6 was inhibited by the unavailability of tocilizumab-free IL-6R. We also concluded that the increased level of free IL-6 during tocilizumab treatment closely reflects the actual endogenous IL-6 production and true disease activity. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: X. Chen, R. Das, R. Komorowski, A. Beres, M. J. Hessner, M. Mihara, and W. R. Drobyski Blockade of interleukin-6 signaling augments regulatory T-cell reconstitution and attenuates the severity of graft-versus-host disease Blood, July 23, 2009; 114(4): 891 - 900. [Abstract] [Full Text] [PDF]

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