Rheumatoid Arthritis (RA) is a progressive and systemic autoimmune disorder associated with chronic and destructive inflammation of the joints. The hallmarks of RA are synovial cell proliferation, extensive neoangiogenesis and infiltration of numerous immune cells into the synovial tissue, including monocyte-derived macrophages. In vitro approaches simulating the RA synovium are crucial in preclinical and translational research to design novel treatment strategies and improve clinical outcomes.
In our group, we focus on mimicking the RA synovial tissue using multicellular 3D systems that recapitulate the cell-cell/cell-matrix interactions, and key pro-inflammatory mediators present in the inflamed synovium. We previously established a spheroid-based model of synovial angiogenesis incorporating human umbilical vein endothelial cells (HUVECs) and RA fibroblast-like-synoviocytes (RAFLSs), which allowed studying non-canonical nuclear factor-kB signaling pathway and testing of small molecular inhibitors (1). We subsequently incorporated monocyte-derived macrophages, major effectors of synovial inflammation through the production of cytokines and pro-inflammatory molecules. This new model aims to mimic the complex interactions between the cell types and dissect their role in inflammatory responses in the context of RA. Ultimately, this organoid approach can be used to test the effects of novel diagnostic (molecular imaging) and therapeutic compounds, including small molecule inhibitors and biologics. Moreover, such approach paves the way for a wide range of applications as alternative cell types or subtypes can be implemented as was previously demonstrated by our group in a 3D model of colorectal cancer angiogenesis.
Team leader
Prof. dr. Sander W. Tas, MD, PhD
Internist-Rheumatologist at the Amsterdam Rheumatology and Immunology Center, Amsterdam UMC location AMC
Prof. Tas is a translational scientist with experience in both basic and clinical translational research. He is one of the Amsterdam UMC Principal Investigators, has an H-index of 31, and wrote >100 scientific articles. Furthermore, he is program leader “inflammatory diseases” of the Amsterdam Infection & Immunity Institute (AMC/VUmc) and member of the EULAR Research Committee. He has multiple connections and collaborations with international scientific groups as well as pharmaceutical companies. His translational research has a strong focus on the molecular regulation of inflammation and includes basic research on signal transduction, in particular the role of NF-kB signaling and other pathways in immune-mediated inflammatory diseases, DC vaccination, studies in animal models of arthritis, DCE-MRI and PET-CT imaging, and state-of-the-art tissue analysis.
Since 2020 he is Vice-Chair of the department of Rheumatology and Clinical Immunology of Amsterdam UMC, which is known for pivotal clinical trials, including proof-of-concept studies in relatively small patient groups and individuals at risk of developing RA, and transformative translational immunology approaches. it is recognized as Center of Excellence, both by the European League against Rheumatism (EULAR) and by the Federation of Clinical Immunology Societies (FOCIS).
Dr. Jan Piet van Hamburg
Senior Scientist at the Amsterdam Rheumatology and Immunology Center, and Department of Experimental Immunology, Amsterdam UMC location AMC
My research focuses on the identification and modulation of inflammatory cells in patients with immune-mediated inflammatory diseases (IMIDs). The main research lines concern the characterization of signaling pathways, with a particular interest for NF-kB signaling in lymphocytes and dendritic cells. For these investigations various assays are used, including spheroid culture systems, which can be used to study various processes and cellular interactions underlying inflammation and angiogenesis in patients with IMIDs.
Team members
Publications
- Silencing NIK potentiates anti-VEGF therapy in a novel 3D model of colorectal cancer angiogenesisObjective: Angiogenesis is crucial in RA disease progression. Lymphotoxin β receptor… »
- Targeting non-canonical nuclear factor-κB signalling attenuates neovascularization in a novel 3D model of rheumatoid arthritis synovial angiogenesisObjective: Angiogenesis is crucial in RA disease progression. Lymphotoxin β receptor… »
Funding
Marie Skłodowska-Curie COFUND ARCAID programme as part of European Horizon 2020, GSK, ReumaNederland.