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

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...

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Autores principales: Lachmann, Helen J., Lowe, Philip, Felix, Sandra Daniela, Rordorf, Christiane, Leslie, Kieron, Madhoo, Sheril, Wittkowski, Helmut, Bek, Stephan, Hartmann, Nicole, Bosset, Sophie, Hawkins, Philip N., Jung, Thomas
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2715040/
https://www.ncbi.nlm.nih.gov/pubmed/19364880
http://dx.doi.org/10.1084/jem.20082481
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author Lachmann, Helen J.
Lowe, Philip
Felix, Sandra Daniela
Rordorf, Christiane
Leslie, Kieron
Madhoo, Sheril
Wittkowski, Helmut
Bek, Stephan
Hartmann, Nicole
Bosset, Sophie
Hawkins, Philip N.
Jung, Thomas
author_facet Lachmann, Helen J.
Lowe, Philip
Felix, Sandra Daniela
Rordorf, Christiane
Leslie, Kieron
Madhoo, Sheril
Wittkowski, Helmut
Bek, Stephan
Hartmann, Nicole
Bosset, Sophie
Hawkins, Philip N.
Jung, Thomas
author_sort Lachmann, Helen J.
collection PubMed
description 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.
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spelling pubmed-27150402009-11-11 In vivo regulation of interleukin 1β in patients with cryopyrin-associated periodic syndromes Lachmann, Helen J. Lowe, Philip Felix, Sandra Daniela Rordorf, Christiane Leslie, Kieron Madhoo, Sheril Wittkowski, Helmut Bek, Stephan Hartmann, Nicole Bosset, Sophie Hawkins, Philip N. Jung, Thomas J Exp Med Brief Definitive Report 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. The Rockefeller University Press 2009-05-11 /pmc/articles/PMC2715040/ /pubmed/19364880 http://dx.doi.org/10.1084/jem.20082481 Text en © 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/).
spellingShingle Brief Definitive Report
Lachmann, Helen J.
Lowe, Philip
Felix, Sandra Daniela
Rordorf, Christiane
Leslie, Kieron
Madhoo, Sheril
Wittkowski, Helmut
Bek, Stephan
Hartmann, Nicole
Bosset, Sophie
Hawkins, Philip N.
Jung, Thomas
In vivo regulation of interleukin 1β in patients with cryopyrin-associated periodic syndromes
title In vivo regulation of interleukin 1β in patients with cryopyrin-associated periodic syndromes
title_full In vivo regulation of interleukin 1β in patients with cryopyrin-associated periodic syndromes
title_fullStr In vivo regulation of interleukin 1β in patients with cryopyrin-associated periodic syndromes
title_full_unstemmed In vivo regulation of interleukin 1β in patients with cryopyrin-associated periodic syndromes
title_short In vivo regulation of interleukin 1β in patients with cryopyrin-associated periodic syndromes
title_sort in vivo regulation of interleukin 1β in patients with cryopyrin-associated periodic syndromes
topic Brief Definitive Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2715040/
https://www.ncbi.nlm.nih.gov/pubmed/19364880
http://dx.doi.org/10.1084/jem.20082481
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