Abatacept blocks anti-citrullinated protein antibody and rheumatoid factor\xa0mediated cytokine production in human macrophages in IDO-dependent manner

Aline Bozec,Yubin Luo,Cecilia Engdahl,Holger Bang,Camille Figueiredo,Georg Schett

doi:10.1186/s13075-018-1527-x

Abstract

BackgroundThe anti-inflammatory effect of abatacept is most pronounced in patients with high-titer autoantibodies (including anticitrullinated protein antibodies [ACPA] and rheumatoid factor [RF]). Considering that autoantibodies trigger inflammatory cytokine production by monocytes and that abatacept binds to monocytes, influencing their functional state, we hypothesized that abatacept may effectively inhibit the production of several different cytokines by ACPA- or RF-challenged monocytes.MethodsPeripheral blood CD68+ monocytes stimulated with macrophage colony-stimulating factor for 24 h were exposed to random immunoglobulin G alone (negative control), purified ACPA, purified RF, or lipopolysaccharide (positive control) in cell culture plates coated with citrullinated vimentin (to allow ACPA immune complex formation). Stimulations were done in the presence or absence of abatacept or tumor necrosis factor (TNF) antibody (adalimumab) with or without indoleamine 2,3-dioxygenase (IDO) inhibitor 1-methyl-d-tryptophan. Supernatants were analyzed for key proinflammatory cytokines TNF-α, interleukin (IL)-1β, IL-6, IL-8, and chemokine (C-C motif) ligand 2 (CCL2) after 24 h.ResultsExposure to ACPA or RF significantly induced the production of TNF-α (20-fold and 27-fold, respectively), IL-1β (each 4-fold), IL-6 (12-fold and 11-fold, respectively), IL-8 (43-fold and 30-fold, respectively), and CCL2 (each 4-fold) in human monocytes. Abatacept inhibited this autoantibody-mediated upregulation of cytokines, reducing TNF-α by > 75%, IL-1β by > 65%, IL-6 and IL-8 by > 80%, and CCL2 by > 60%. In contrast, a TNF inhibitor did not influence autoantibody-induced proinflammatory cytokine production. IDO inhibition reversed the effect of abatacept and again permitted the induction of cytokine production by ACPA and RF.ConclusionsThese data show that abatacept interferes with autoantibody-mediated cytokine production by monocytes through induction of IDO. This inhibitory effect on the production of several effector cytokines in RA may explain the fast anti-inflammatory effect of abatacept as well as its preferential efficacy in patients with high-titer ACPA and RF.

Highlights

The anti-inflammatory effect of abatacept is most pronounced in patients with high-titer autoantibodies
Exposure to either anticitrullinated protein antibodies (ACPA) or rheumatoid factor (RF) led to a multifold increase in the production of tumor necrosis factor (TNF)-α (20-fold and 27-fold, respectively), IL-1β, IL-6 (12-fold and 11fold, respectively), IL-8 (43-fold and 30-fold, respectively), and Chemokine ligand 2 (CCL2) by monocytes (Fig. 1)
Abatacept concentrations resembling serum concentrations in patients with Rheumatoid arthritis (RA) treated with abatacept significantly inhibited the production of TNF-α (−77%), IL-1β (−65%), IL-6 (−83%), IL-8 (−83%), and CCL2 (−71%) by monocytes stimulated with ACPA

Summary

Introduction

The anti-inflammatory effect of abatacept is most pronounced in patients with high-titer autoantibodies (including anticitrullinated protein antibodies [ACPA] and rheumatoid factor [RF]). Previous data have shown that both complexes of anticitrullinated protein antibodies (ACPA) and rheumatoid factor (RF) induce robust cytokine production from human macrophages [5,6,7,8,9]. This effect is mediated by the cross-linking of Fcγ receptor IIa on macrophages, representing a strong activation signal for cytokine release [6]. Newer data suggest that macrophage colony-stimulating factor (M-CSF)-primed macrophages are sensitive to immune complex-mediated cytokine production, an observation that is reflected by the local milieu in the synovial membrane of patients with RA, where large amounts of M-CSF are present [5, 10]. The leading role of autoantibodies in triggering cytokine release in patients with RA is reflected by clinical observations which show that patients with RA with autoantibodies exhibit a more severe disease course [1]

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Discussion

Conclusion