Steroid Refractory CD4+T Cells in Patients with Sight-Threatening Uveitis

Abstract

A discrete subpopulation of steroid refractory (SR) CD4(+) T cells has recently been identified in patients with SR ulcerative colitis (UC). The purpose of this study was to test whether this subpopulation is also present in patients with clinically defined SR uveitis. As interleukin (IL)-2 experimentally mediates the SR phenotype, the combined effects of dexamethasone (Dex) and a range of IL-2 targeting immunosuppressive agents were also investigated. Peripheral blood mononuclear cells (PBMCs) from 27 patients with uveitis and 4 normal volunteers were cultured for 5 days with CD3-CD28 beads. In vitro steroid refractivity or responsiveness was determined by the presence or absence of a subpopulation of SR CD4(+) cells (as previously reported for UC) that continued to proliferate or not in the presence of Dex. The patients were concurrently classified by a masked investigator as having clinically SR (threshold for disease reactivation, >or=10 mg prednisone daily) or steroid sensitive (SS) disease. There was 78% (21/27) agreement between the in vitro and clinical classifications of SR and SS disease (kappa coefficient = 0.56, P = 0.002). This finding corresponds to a positive predictive value of 90% and a negative predictive value of 71%. In normal volunteers, basiliximab, daclizumab, and AG490 achieved an equivalent augmentation of CD4(+) cell suppression in combination with Dex. As in UC, patients with SR uveitis have a subpopulation of SR CD4(+) cells that are a potential target for intervention with anti-IL-2 therapies, including inhibitors of JAK/STAT signaling. The identification of SR T cells also has potential clinical application as a biomarker for SR disease.