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Interleukin-1 antagonism moderates the inflammatory state associated with Type 1 diabetes during clinical trials conducted at disease onset

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  • Type 1 Diabetes TrialNet Canakinumab Study Group (Lise Tarnow, members)
  • The AIDA Study Group (Flemming Pociot, members)
  • Flemming Pociot (Member of study group)
  • Jørgen Rungby (Member of study group)
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It was hypothesized that IL-1 antagonism would preserve β-cell function in new onset Type 1 diabetes (T1D). However, the Anti-Interleukin-1 in Diabetes Action (AIDA) and TrialNet Canakinumab (TN-14) trials failed to show efficacy of IL-1 receptor antagonist (IL-1Ra) or canakinumab, as measured by stimulated C-peptide response. Additional measures are needed to define immune state changes associated with therapeutic responses. Here, we studied these trial participants with plasma-induced transcriptional analysis. In blinded analyses, 70.2% of AIDA and 68.9% of TN-14 participants were correctly called to their treatment arm. While the transcriptional signatures from the two trials were distinct, both therapies achieved varying immunomodulation consistent with IL-1 inhibition. On average, IL-1 antagonism resulted in modest normalization relative to healthy controls. At endpoint, signatures were quantified using a gene ontology-based inflammatory index, and an inverse relationship was observed between measured inflammation and stimulated C-peptide response in IL-1Ra- and canakinumab-treated patients. Cytokine neutralization studies showed that IL-1α and IL-1β additively contribute to the T1D inflammatory state. Finally, analyses of baseline signatures were indicative of later therapeutic response. Despite the absence of clinical efficacy by IL-1 antagonist therapy, transcriptional analysis detected immunomodulation and may yield new insight when applied to other clinical trials.

Original languageEnglish
JournalEuropean Journal of Immunology
Volume46
Issue number4
Pages (from-to)1030-46
Number of pages17
ISSN0014-2980
DOIs
Publication statusPublished - Apr 2016

Bibliographical note

© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

    Research areas

  • Adult, Antibodies, Monoclonal, Cells, Cultured, Diabetes Mellitus, Type 1, Humans, Immunotherapy, Inflammation, Insulin-Secreting Cells, Interleukin 1 Receptor Antagonist Protein, Interleukin-1alpha, Interleukin-1beta, Male, Clinical Trial, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't

ID: 49459749