DS0410 -

Investigation of in vivo human type I interferon production and control in the type I interferonopathies – IFNX

Submission summary

Type I interferons (IFNs) have long been recognised as key immune mediators, in particular in anti-viral defence. Due to their potent and broad effect the IFN response operates along a spectrum, and must be balanced between protection against infection versus risk of inflammatory disease and immunopathogenesis. As such, the induction, transmission, and resolution of IFN responses are tightly regulated. Type I interferonopathies and related non-monogenic phenotypes represent examples of a disturbance of the homeostatic control of this complex system. The identification of such diseases is of clinical importance as ‘anti-IFN’ treatments are developed based on an understanding of pathology. Furthermore, these diseases provide an unprecedented opportunity to define the role of type I IFNs in human health and disease.

Despite their key roles in immune defence and human pathology, no routine laboratory test exists in medical practice for the assessment of type I IFN signalling. We will take advantage of a breakthrough technology, digital ELISA that permits for the first time the direct quantification of type I IFN proteins in human samples. We emphasize here the true novelty of this approach, which is based on ex vivo analysis in a human context to dissect out the regulation and function of IFNs in a range of diverse disease settings. We present compelling preliminary data demonstrating the potential use of this revolutionary platform, and highlight the exceptional patient cohorts that we have established which will enable us to pursue these studies. Importantly, this proposal will provide new information about the role and cellular sources of different IFNs, how IFN-stimulated signals are transduced, and the engagement of feedback loops during therapeutic intervention. Previous studies have addressed some of these questions with transcriptomic approaches, but an assessment at the functional proteomic level has not been possible until now.

We believe that our proposed approach using the Simoa platform represents a technological step-change, which has major significance for the future diagnosis and treatment of patients with disease related to an upregulation of type I IFN signalling, and in the study of underlying mechanisms relevant to these disorders. With a focus on diagnostics, stratification and target identification, we consider that our application has remarkable potential for translation into near-term clinical benefit.

Project coordinator

Monsieur Yanick CROW (Institut National de la santé et de la recherche médicale)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

INSTITUT PASTEUR (BP)
INSERM DR PARIS 5 - UMR1163 IHU IMAGINE - Crow Institut National de la santé et de la recherche médicale

Help of the ANR 575,322 euros
Beginning and duration of the scientific project: October 2016 - 36 Months

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