From harassing to harnessing beta-cells in type 1 diabetes

Projektbeschreibung

„Gestresste“ β-Zellen für das Immunsystem unsichtbar machen, um Typ-1-Diabetes zu verhindern

Typ-1-Diabetes ist die Folge einer Autoimmunreaktion, bei der das körpereigene Immunsystem die Insulin produzierenden β-Zellen in der Bauchspeicheldrüse angreift und zerstört. Eine Immuntherapie hat sich bei der Prävention als nicht erfolgreich erwiesen. Das ERC-finanzierte Projekt Beta-STEALTH zielt darauf ab, seiner jüngsten Entdeckung auf den Grund zu gehen – „gestresste“ β-Zellen produzieren Neoantigene, die das körpereigene Immunsystem so provozieren, dass es sich um eine natürliche und nicht um eine aberrante Reaktion handelt. Der Schwerpunkt liegt auf diesen DRiP-Antigenen (defective ribosomal product, fehlerhaftes ribosomales Produkt). Im Rahmen des Projekts werden die Mechanismen ihrer Produktion und Wirkung, potenzielle, DRiP anvisierende Diagnoseinstrumente sowie Therapien, einschließlich gezielter Arzneimittelverabreichung, selektiver Immuntherapie und Zelltherapie mittels Genomeditierung, untersucht.

Ziel

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