Glucose metabolism as a biomarker for optimal tolDC functionality

Rheumatoid arthritis (RA) is a chronic autoimmune disease of the joints which affects approximately 1% of the world population. Current treatment strategies for RA amount to symptomatic relief, but do not cure the disease. Consequently, RA patients are subjected to life-long immunosuppressive therapy at the cost of elevated risks of cancer and infections, and unpleasant side-effects.

Next-generation therapeutic strategies aim at curing RA by restoring the disrupted immune balance. Cell therapy using autologous antigen-loaded tolerogenic dendritic cells (tolDC) is the leading approach. We previously showed that these cells are therapeutically effective in animal models of RA and are currently testing their safety and immunological efficacy in a first-in-man phase I/IIa clinical trial in RA patients.

Despite these advances, it remains unclear what exactly confers therapeutic tolDC their tolerogenic functionality. Our preliminary data, and prior research by others, indicate that tolDC exhibit a unique metabolism.

We aim to explore if cellular metabolism, glucose metabolism specifically, relates to the functional potency of tolDC. We will perform advanced metabolic and transcriptomic profiling of tolDC. Subsequently, we will interfere with the characterized pathways and analyse tolDC functionality in our previously developed tolDC potency assay. Additionally, we will study the metabolic and functional impact of prominent anti-rheumatic drugs on tolDC from healthy donors and RA patients. The results of this project will grant fundamental insights into tolDC metabolism related to potency. We anticipate these insights asindispensable for the future development of theragnostic and quality control assays. Observed effects of anti-rheumatic medication will be crucial for targeting tolDC therapy to the best-suited patients.

Combined, this project will boost the technological readiness and societal readiness of tolDC as a first-of-its-kind curative therapy for RA.

Fenne Verheijen