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Sebastiaan Vastert

Thursday 30 May 2013

Mechanisms of disease and therapy in severe JIA

Promotor: Prof.dr B.J. Prakken
Defence: 30 May 2013

This thesis presents results of translational research (both bench to bedside and vice versa from the bed back to the bench) in severe juvenile idiopathic arthritis (JIA). It focuses on understanding key immunological features of both systemic and polyarticular JIA and seeks to relate this to the current and new therapeutic interventions in patients.
In systemic JIA (sJIA), we focused on the apparent paradox of increased interleukin-18 (IL-18) plasma levels and concomitant deficient function of natural killer (NK) cells. Normally, IL-18 is important for the activation of NK cells and increases the lytic function of NK cells. In patients with sJIA this is not the case. In this thesis, we have demonstrated that the mechanism of reduced NK-cell function in sJIA is based on a defect in the activation of the receptor for IL-18. Next, we demonstrated that treatment with an IL-1 blocker, Anakinra or rIL-1RA, restores the impaired IL-18-NK cell axis in sJIA , by binding to the IL-18 receptor. In a prospective cohort study with rIL-1RA as first-line treatment in patients with sJIA we have shown that rIL-1RA is very effective when started early in the course of the disease and, moreover, that in the majority of our patients, treatment with rIL -1RA could be stopped within 12 months while maintaining good response.
The second part of this thesis investigates immunological effects of the three major therapeutical regimes in severe JIA, specifically on the function and the number of both regulatory T cells (Treg) and effector T cells (Teff).
First we show evidence that methotrexate (MTX) exerts not an immunosuppressive effect, but an immune modulating or stimulating effect on T cell subsets in patients with severe polyarticular JIA.
Then we showed in a study in which both blood and synovial fluid samples from patients have been studied, that anti-TNF therapy (etanercept) targets the resistance of Teff to suppression by Treg.
Finally, we studied the immune reconstitution of 12 patients undergoing autologous stem cell transplantation for severe, refractory JIA. We found that at least two mechanisms contribute to the therapeutic effect of this treatment, a preferential reconstitution of the regulatory T-cells in the first 12 months after ASCT and the induction or change of a specific HSP60 peptide T cell response, of a pro- inflammatory response to HSP60 before ASCT to a more tolerant T-cell response after ASCT. This indicates that ASCT the disturbed balance between Teff and Treg in severe, refractory JIA recovers.