Interleukin-1 antagonism moderates the inflammatory state associated with Type 1 diabetes during clinical trials conducted at disease onset
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Interleukin-1 antagonism moderates the inflammatory state associated with Type 1 diabetes during clinical trials conducted at disease onset. / Cabrera, Susanne M; Wang, Xujing; Chen, Yi-Guang; Jia, Shuang; Kaldunski, Mary L; Greenbaum, Carla J; Mandrup-Poulsen, Thomas; Hessner, Martin J.
In: European Journal of Immunology, Vol. 46, No. 4, 04.2016, p. 1030-1046.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Interleukin-1 antagonism moderates the inflammatory state associated with Type 1 diabetes during clinical trials conducted at disease onset
AU - Cabrera, Susanne M
AU - Wang, Xujing
AU - Chen, Yi-Guang
AU - Jia, Shuang
AU - Kaldunski, Mary L
AU - Greenbaum, Carla J
AU - Mandrup-Poulsen, Thomas
AU - Hessner, Martin J
N1 - © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
PY - 2016/4
Y1 - 2016/4
N2 - 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.
AB - 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.
KW - Adult
KW - Antibodies, Monoclonal
KW - Cells, Cultured
KW - Diabetes Mellitus, Type 1
KW - Humans
KW - Immunotherapy
KW - Inflammation
KW - Insulin-Secreting Cells
KW - Interleukin 1 Receptor Antagonist Protein
KW - Interleukin-1alpha
KW - Interleukin-1beta
KW - Male
KW - Clinical Trial
KW - Journal Article
KW - Research Support, N.I.H., Extramural
KW - Research Support, Non-U.S. Gov't
U2 - 10.1002/eji.201546005
DO - 10.1002/eji.201546005
M3 - Journal article
C2 - 26692253
VL - 46
SP - 1030
EP - 1046
JO - European Journal of Immunology
JF - European Journal of Immunology
SN - 0014-2980
IS - 4
ER -
ID: 167806067