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Interleukin-6 receptor inhibition restores the kinase activity signature of CD4

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Interleukin-6 receptor inhibition restores the kinase activity signature of CD4

+

T cells and promotes migration of regulatory T cells in rheumatoid arthritis With a global annual incidence rate of around 1%, rheumatoid arthritis (RA) leads to severe disabilities and premature mortality. Animal studies have demonstrated the critical role of Th17 cells and the role of interleukin-6 (IL-6) in their development. Inhibition of the IL-6 receptor-signaling pathway improves autoimmune arthritis in animal models. Moreover, as IL-6 is a key player of immune activation and inflammation. Targeting the IL-6 signaling axis by inhibiting the IL-6 receptor has become a compelling strategy to treat RA. Treatment with the IL-6 receptor blocker tocilizumab normalizes inflammatory markers as well as increases IL-6 secretion while IL-6 mRNA expression is not affected. Albeit the broad knowledge of IL-6 and its role in inflammation is immense, only little is known about the influence of IL-6 and the blockade of the IL-6 receptor on kinase activity.

The aim of this study was to identify kinases and kinase networks that show altered activity in RA in order to identify potential new candidates for targeted therapy approaches. The results of the kinase activity assay show for the first time that treatment with tocilizumab not only restores regulatory T cell (T

reg

) frequencies and diminishes Th17 cell numbers in the peripheral blood but also promotes migratory functions of CD4

+

T cells from RA patients by altering the kinase activity signature. Furthermore, we identified kinases (GPSM2, VTNC, and PTK6) with a significantly altered kinase activity in RA patients, when compared to healthy individuals.

Those kinases might be promising new candidates for targeted therapy approaches.

In summary, this study provides further evidence, that treatment with tocilizumab not only

improves the patient’s outcome but also changes the kinase activity signature of CD4

+

T cells

dramatically. Kinome analysis reveals a specific ex vivo kinase activity and IL-6R inhibition

restores the specific kinase activity signature. These findings also give new insight into the

migratory functions of CD4

+

T cells in RA. Additionally, IL-6R inhibition promotes T

reg

cell

migration towards specific chemokines in patients with RA. Finally, kinome profiling identifies

new potential candidates for targeted and advanced therapy of RA.

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