A1.6 IDO Pathway in RA Patients Responding to Biologic Treatments

Abstract

<h3>Background and Objectives</h3> Indoleamine 2,3-dioxygenase (IDO) is an enzyme involved in immune tolerance, which is thought to be defective in Rheumatoid Arthritis (RA). It is expressed in mononuclear cells including dendritic cells (DC), and could play a role in DC-regulatory T cells crosstalk. Our aim was to study IDO expression in peripheral blood of patients with RA compared to controls. Effect of biotherapies on IDO was also evaluated under anti-rheumatic biotherapies. <h3>Methods</h3> Human PBMC were purified by density gradient centrifugation and IDO gene expression was assessed by qRT-PCR. In parallel, the dosage of kynurenine was performed in plasma to evaluate IDO activity. For some patients, PBMC were cultured for 24 hours with LPS, IFNγ or both before IDO assays. <h3>Results</h3> We included 40 patients with RA and 30 controls including 15 spondylarthropathies (SpA), 10 osteoarthritis (OA) and 5 osteoporosis (OP). Our results showed that IDO was over-expressed and more active in RA than in non inflammatory diseases. Interestingly, in RA patients, before treatment with biotherapies, kynurenine plasmatic levels were negatively correlated with the DAS28 activity score (r = –0.552; p &lt; 0.016), and IDO mRNA ratio with ESR (r = –0.536; p &lt; 0.003). After 3 months of biologics (independently of treatments), kynurenine levels significantly decreased in responders, while they remained unchanged in non responders. In anti-TNFα-treated RA patients (n = 10), IDO mRNA was significantly decreased after 3 months whereas in tocilizumab (IL-6 receptor-inhibitor, n = 17) or abatacept (CTLA4-Ig; n = 10) treated patients, IDO levels did not change significantly. <h3>Conclusions</h3> IDO was up-regulated and more functional in patients with RA. It was negatively correlated with systemic inflammation and disease activity. IDO gene expression was also more inducible in this group of patients. So, in RA, IDO could contribute to decrease systemic inflammation and disease activity in a counter-regulation loop (which needs to be confirmed in further experiments). Tocilizumab and abatacept exerted an IDO-independent protection, whereas after an anti-TNFα treatment, IDO expression and inductibility decreased. This could help in treatment strategies in RA.