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

• Published in: European journal of immunology 2016-04, Vol.46 (4), p.1030-1046
• Main Authors: Cabrera, Susanne M., Wang, Xujing, Chen, Yi‐Guang, Jia, Shuang, Kaldunski, Mary L., Greenbaum, Carla J., Mandrup‐Poulsen, Thomas, Hessner, Martin J.
• Format: Article
• Language: English
• Subjects: Adult; Anakinra; Antibodies, Monoclonal - therapeutic use; Antibodies, Monoclonal, Humanized; Beta cells; Canakinumab; Cells, Cultured; Clinical trials; Cytokines; Diabetes; Diabetes mellitus; Diabetes Mellitus, Type 1 - drug therapy; Diabetes Mellitus, Type 1 - immunology; Humans; Immunomodulation; Immunotherapy - methods; Inflammation; Inflammation - immunology; Inhibition; Insulin-Secreting Cells - physiology; Interleukin 1; Interleukin 1 receptor antagonist; Interleukin 1 Receptor Antagonist Protein - therapeutic use; Interleukin-1alpha - immunology; Interleukin-1beta - antagonists & inhibitors; Interleukin-1beta - immunology; Male; Medicin och hälsovetenskap; Neutralization; Transcription; Transcriptional signatures; Type 1 diabetes
• ISSN: 0014-2980; 1521-4141; 1521-4141
• DOI: 10.1002/eji.201546005

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. Measures of immune efficacy are needed in Type 1 Diabetes clinical trials. Using a plasma‐based bioassay, we provide evidence of immune modulation in the Anti‐Interleukin‐1 in Diabetes Action and TrialNet Canakinumab trials which failed to show efficacy of IL‐1 receptor antagonist (IL‐1Ra) or canakinumab, as traditionally measured by stimulated C‐peptide response.