The Journal of Experimental Medicine
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Published online
doi:10.1084/jem.20082481
The Journal of Experimental Medicine, Vol. 206, No. 5, 1029-1036
The Rockefeller University Press, 0022-1007 $30.00
© Lachmann et al.
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BRIEF DEFINITIVE REPORT

 In vivo regulation of interleukin 1β in patients with cryopyrin-associated periodic syndromes

Helen J. Lachmann1, Philip Lowe2, Sandra Daniela Felix3, Christiane Rordorf3, Kieron Leslie4, Sheril Madhoo1, Helmut Wittkowski5, Stephan Bek3, Nicole Hartmann3, Sophie Bosset3, Philip N. Hawkins1, and Thomas Jung3

1 National Amyloidosis Centre, Royal Free and University College Medical School, London NW3 2PF, England, UK
2 Novartis Development, Modeling, and Simulation and 3 Novartis Institutes of Biomedical Research, Translational Sciences, Forum 1, CH-4002 Basel, Switzerland
4 Department of Dermatology, University of California, San Francisco, San Francisco, CA 94110
5 Institute of Immunology, University of Münster, D-48149 Münster, Germany

CORRESPONDENCE Thomas Jung: thomas.jung{at}novartis.com

The investigation of interleukin 1β (IL-1β) in human inflammatory diseases is hampered by the fact that it is virtually undetectable in human plasma. We demonstrate that by administering the anti–human IL-1β antibody canakinumab (ACZ885) to humans, the resulting formation of IL-1β–antibody complexes allowed the detection of in vivo–produced IL-1β. A two-compartment mathematical model was generated that predicted a constitutive production rate of 6 ng/d IL-1β in healthy subjects. In contrast, patients with cryopyrin-associated periodic syndromes (CAPS), a rare monogenetic disease driven by uncontrolled caspase-1 activity and IL-1 production, produced a mean of 31 ng/d. Treatment with canakinumab not only induced long-lasting complete clinical response but also reduced the production rate of IL-1β to normal levels within 8 wk of treatment, suggesting that IL-1β production in these patients was mainly IL-1β driven. The model further indicated that IL-1β is the only cytokine driving disease severity and duration of response to canakinumab. A correction for natural IL-1 antagonists was not required to fit the data. Together, the study allowed new insights into the production and regulation of IL-1β in man. It also indicated that CAPS is entirely mediated by IL-1β and that canakinumab treatment restores physiological IL-1β production.

© 2009 Lachmann et al.
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).


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