- Identify the effects of regulatory-protective TH2 cytokines on synovium metabolism and on bone and cartilage degradation.
- Analyze the endogenous moduclation of the expression of TH2 cytokines.
- Evaluate the role of TH2 cytokines in vivo.
Rheumatoid arthritis (RA) is the most common and severe form of inflammatory arthritis, affecting 3 million patients in Europe. Unresolved questions to improve its treatment are the identification of the events leading to the induction and perpetuation of the disease. Proinflammatory cytokines produced by the synovitis have a direct effect on joint destruction. This appears to be the consequence of a shift in the T cell derived cytokine balance. The regulatory TH2 cytokines IL 4, IL 10, IL 13 have shown interesting beneficial effects. Such results have to be extended to demonstrate how these cytokines may be protective in vivo. Furthermore, as an improvement of RA is seen in conditions such as pregnancy where a switch from TH1 to TH2 may occur, the identification of conditions able to induce such switch may represent a way to control disease. Ex-vivo and in-vitro models will be used to analyze the effects of TH2 cytokines on the release of cytokines, enzymes and their inhibitors, and extracellular matrix degradation products. To dissect the in-vivo interactions, similar studies will be performed using cocultures of monocytes and Th classified T cell clones with mesenchymal cells. This will define to what extent these cytokines are beneficial and how they differ from each other. The second task will select conditions able to induce the endogenous production and activity of TH2 cytokines. The contribution of cytokine polymorphisms on pro and anti-inflammatory cytokine balance in this effect will be investigated. The goal of this task is to analyze how the induction of this endogenous production is possible and whether this is also protective. The third task is the extension of these results to the in vivo situation using animal models to determine how such modulation can lead to a beneficial effect of clinical interest in RA.
Funding SchemeCSC - Cost-sharing contracts
6525 GA Nijmegen
S10 2JF Sheffield