From harassing to harnessing beta-cells in type 1 diabetes

Description du projet

Rendre les cellules β «stressées» invisibles au système immunitaire pour prévenir le diabète de type 1

Le diabète de type 1 résulte d’une réponse auto-immune qui conduit le système immunitaire de l’organisme à cibler et à détruire les cellules β productrices d’insuline dans le pancréas. L’immunothérapie n’a pas permis de la prévenir. Le projet Beta-STEALTH, financé par le CER, entend étudier sa récente découverte selon laquelle les cellules β «stressées» produisent des néoantigènes qui provoquent le système immunitaire de l’organisme, ce qui en fait une réponse naturelle plutôt qu’aberrante. L’accent sera mis sur ces néoantigènes de type «produit ribosomique défectueux» (DRiP pour «defective ribosomal product»). Le projet examinera les mécanismes de leur production et de leur action, les outils de diagnostic potentiels ciblant le DRiP et les thérapies, y compris l’administration ciblée de médicaments, l’immunothérapie sélective et la thérapie cellulaire utilisant l’édition de gènes.

Objectif

Type 1 diabetes (T1D) is generally believed to result from a mistake by the immune system leading to the autoimmune destruction of insulin-producing β-cells in the pancreatic islets of Langerhans. Based on my discoveries, I recently began to realise that the ‘mistake’ actually occurs in stressed β-cells, leading to the generation of neoantigens resulting from ribosomal infidelity (DRiP) that provoke the immune system to act. The immune system may actually respond with ‘good’ intentions, similar to the response to such neoantigens generated upon infection and in cancer. This could explain why immune intervention therapy alone has been quite disappointing in T1D, where the loss in β-cell function could at best only be delayed. I contend that we will need β-cell therapy for a durable intervention or even remission, likely in concert with immunotherapy, to keep β-cells from provoking the immune system. Thus, I propose to explore β-cell stress, autoimmunity, resilience and function in three levels:
Pathogenesis: understand the association of protective insulin gene variation with reduced β-cell stress and immunogenicity; explore the nature and function of β-cell stress product DRiP in β-cell development, heterogeneity, function and destruction;
Diagnostics: target DRiP to detect β-cell stress, immunogenicity and destruction; monitor autoimmunity to DRiP by islet autoreactive T-cells or autoantibodies;
Therapeutics: develop targeted delivery of drugs to distressed β-cells to foster recovery, mass and function and increase their stamina; restore immune tolerance by selective immunotherapy with islet neoantigens; generate a novel source of stem cell derived β-cells that have been equipped with resilience and superior function by gene-editing to reduce both stress and generation of neoantigens.
Through these objectives, I intend to eliminate the reasons for the immune system to harass β-cells by harnessing β-cells and turn these invisible (‘stealth’) to the immune system