Immune Avatar - Make your immune system GREAT again - Entwicklung einer in-vitro Wirkstoff-Testplattform zur patientenspezifischen Modellierung der Nichtalkoholischen Steatohepatitis und chronischer Darmerkrankungen in einem immunkompetenten Leber-Fett-Darm Organmodell

Abstract

The Immune Avatar consortium was launched to allow for the generation and validation of immunocompetent in vitro models of the liver, intestine and adipose tissue crosstalk for drug candidate testing, particularly for metabolic diseases. The project thus aimed at tackling a current lack of multicellular, human cell-based, metabolically functional and clinically-relevant models that would also integrate the crucial and diverse roles of the immune system in disease progression or drug response. Due to logistical and technical challenges, we at Charité had to postpone the use of primary human material and instead focused on primary mouse cells. Yet, this contingency plan led us to go beyond the initial plan in terms of depth of phenotypical analyses and to further explore the versatility of the system. By doing so, we were able to demonstrate the liver-on-a-chip (LoC) potential to drastically increase the clinical relevance of organ-on-a-chip models as compared to monocellular or conventional 3-dimensional (i.e., organoid) cell culture systems. In particular, our LoC could recapitulate all hallmarks of acute drug-induced liver injury, including circulating immune cell recruitment. Furthermore, we could also model steatosis and demonstrate the potential of drug candidates, lanifibranor and resmetirom, in differentially preventing disease onset. This data has been published in an original research paper, along with detailed technical procedures allowing other institutes to implement the model in their procedures. Overall, we demonstrated the functional relevance of the LoC for disease mechanism study and for preclinical drug candidate evaluations. Current projects in our department build on these successes and explore further applications as well as further optimization of the system to model other conditions. Datei-Upload durch TIB