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Region Hovedstaden - en del af Københavns Universitetshospital
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Interleukin-1 antagonism moderates the inflammatory state associated with Type 1 diabetes during clinical trials conducted at disease onset

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

DOI

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  • Type 1 Diabetes TrialNet Canakinumab Study Group (Lise Tarnow, members)
  • The AIDA Study Group (Flemming Pociot, members)
  • Flemming Pociot (Medlem af forfattergruppering)
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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.

OriginalsprogEngelsk
TidsskriftEuropean Journal of Immunology
Vol/bind46
Udgave nummer4
Sider (fra-til)1030-46
Antal sider17
ISSN0014-2980
DOI
StatusUdgivet - apr. 2016

ID: 49459749