PM.20.054 – Targeting auto-immune driven microvascular disease and fibrosis in Systemic Sclerosis

Route: Personalised medicine: the individual at the centre

Cluster question: 098 How can we use breakthroughs in basic biomedical research to develop new medicines?

Microvascular disease is an important feature of many autoimmune diseases and one of the earliest signs of pathology in patients developing Systemic Sclerosis (SSc). SSc is a severely debilitating disease and carries the highest death burden amongst the rheumatic diseases with currently no prospect for cure. Microvascular disease and immune dysregulation precede tissue fibrosis, which is mostly irreversible. Understanding the early events leading to pathology holds the promise to initiate early intervention and prevention of tissue damage. Strikingly, the presence of both autoantibodies and microvascular damage predict progression towards full-blown SSc, making it plausible that both features are causally linked. Here, we intend to unravel the molecular mechanisms underlying immune-mediated vasculopathy in SSc and to define specific immune markers for prognostication of the development of full-blown SSc with tissue fibrosis. We have recently established novel endothelial cell assays, including microvessels-on-a-chip, that offer the opportunity to evaluate effects of patient-derived factors, such as antibodies, on endothelial cell integrity in a high-throughput manner. By combining these techniques with expertise in immunology (LUMC) and pharmacology (Leiden University) and well-defined patient populations of SSc (LUMC), we create the unique opportunity to place disease-relevant pathophysiological processes directly in the disease context. By doing so, we intend to unravel causal associations between auto-immunity and microvascular disease and eventually fibrosis. We aim to come to improved prediction of disease progression in SSc, a better patient stratification that is based on biological disease mechanisms, and to the identification of novel treatment targets. Investment in these key enabling technologies and assets will, thus, contribute to the Dutch National Research Agenda routes:“Personalised medicine: the individual at the centre” and “Regenerative medicine:game changer moving to broad areas of application’.

Keywords

Autoantibodies, Endothelial cells, fibrosis, Microvascular Disease, Systemic Sclerosis

Other organisations

LACDR, Leiden University (LEI)

Submitter

Organisation Leiden University Medical Center (LUMC)
Name Dr. J.K. (Jeska) de Vries-Bouwstra
E-mail j.k.de_vries-bouwstra@lumc.nl