Targeted Inhibition of Intracellular Kinase Activity in Ankylosing Spondylitis

• Applicant: Dr. Ariane Hammitzsch
• Subject Area: Rheumatology ; Immunology
• Term: from 2013 to 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 238299830

Spondylarthritis (SpA) is a group of rheumatic diseases, which lead to painful inflammation and debilitating new bone formation of joints and spine. This group of diseases includes ankylosing spondylitis (AS) and psoriatic arthritis (PsA). Next to rheumatoid arthritis (RA) they are the most common rheumatic diseases affecting especially young people. Currently only non-steroidal anti-rheumatic drugs (NSARs), such as diclofenac, or tumor necrosis factor (TNF) blockers are available for therapy of AS in contrast to RA. As only two thirds of patients respond well to TNF blockade and as this therapeutic mechanism cannot stop new bone formation, there is an urgent demand for new therapeutic concepts. Inhibition of intracellular kinases like janus kinase (JAK) and spleen tyrosine kinase (SYK), which are involved in the intracellular transmission of proliferative and activating signals, recently demonstrated high therapeutic efficacy in RA. In this regard it is reasonable to investigate the impact of targeted inhibition of these kinases in spondylarthritis. The proposed project aims therefore to test the cellular effects of JAK and SYK inhibition on cells of the innate and acquired immune system as well as on cells of bone metabolism of patients with AS in comparison to RA, PsA and healthy controls.The proposed project focuses on T helper 17 cells, macrophages, natural killer cells, osteoclasts and osteoblast. These cell populations will be either directly isolated from peripheral blood of patients with AS, RA, PsA and healthy controls or generated in vitro from isolated precursors. After activation in the presence or absence of specific kinase inhibitors, cellular effector functions such as production of pro-inflammatory cytokines will be tested and compared. Subsequently the cell populations will be analyzed for changes in expression patterns of specific surface molecules. In a next step differences in phosphorylation of downstream molecules of signaling pathways in response to stimulation with inflammatory mediators will be evaluated. In addition changes of expression patterns of cell population characteristic transcription factors and functional capacities of the cells will be analyzed. The collected data should provide sufficient information to gain deep insight into the pathogenesis of AS and to evaluate whether a therapeutic approach based on targeted inhibition of JAK and SYK kinases by small molecules might be considered as an alternative treatment of AS. In particular it should be clarified whether in AS the inhibition of these intracellular kinases might act in combination with anti-inflammatory effects on the immune system to prevent new bone formation. The data will have broad implication for design of an effective therapy that might prevent permanent functional restriction in AS.

• DFG Programme: Research Fellowships
• International Connection: United Kingdom
• Host: Professor Dr. Paul Bowness