Inhibition of Leukotriene B4–Receptor Interaction Suppresses the Experimental Autoimmune Uveitis (EAU) Induced by Uveitogenic T Cells

Abstract

Abstract: : Purpose: To determine whether inhibition of the migration of interphotoreceptor retinoid binding protein (IRBP)–specific autoreactive T cells and non–specific inflammatory cells by specific leukotriene B₄ (LTB₄) antagonist CP–105, 696 could inhibit established EAU. Methods: Uveitis was induced by injection of IRBP1–20–specific T cells to B6 mouse. The mice were then fed daily with CP–105,696 or placebo at the beginning of T cell transfer or at the disease onset for 15 days. Incidence and severity of uveitis were also studied in the mice transferred with uveitogenic T cells derived from B6 mice to LTB4–receptor (BLT)–deficient mice and vice versa. The disease course was recorded by fundoscopy and histology examination. In addition, the chemoattractive effect of LTB4 and CCL–21 on uveitogenic T cells was compared in vitro assay system. Results: Disease severity in the CP–105,696–treated mice was dramatically reduced by up to 72% to 83% following a 30 day observation. Likewise, the disease incidence and severity were significantly reduced in B6 recipients receiving T cells derived from BLT–deficient mice and in the BLT–deficient mice receiving T cells derived from B6 mice, indicating that deficiency of the migration of either uveitogenic T cells or non–specific inflammatory cells may lead to inhibition of the disease. In vitro studies have shown that CP–105,696 inhibited activated but not naïve uveitogenic T cells. In comparison to CCL–21, which attracts only T cells, CP105,696 predominantly attracted PMN. Conclusions: Treatment of uveitis with a LTB₄ antagonist effectively reduced severity of established uveitis by inhibiting the migration of uveitogenic T cells and PMN.

Keywords: immunomodulation/immunoregulation • inflammation • uveitis-clinical/animal model