Uveitis is an
inflammation of the middle layer of the eye with a high risk of
blindness. The Gi
protein associated A3
adenosine receptor (A3AR) is highly expressed in inflammatory cells whereas low expression is found in normal cells.
CF101 is a highly specific agonist at the A3AR known to induce a robust anti-inflammatory effect in different experimental animal models. The
CF101 mechanism of action entails down-regulation of the NF-κB-TNF-α signaling pathway, resulting in inhibition of pro-inflammatory
cytokine production and apoptosis of inflammatory cells. In this study the effect of
CF101 on the development of
retinal antigen interphotoreceptor retinoid-binding protein (IRBP)-induced experimental autoimmune
uveitis (EAU) was assessed. Oral treatment with
CF101 (10 µg/kg, twice daily), initiated upon disease onset, improved
uveitis clinical score measured by fundoscopy and ameliorated the pathological manifestations of the disease. Shortly
after treatment with
CF101 A3AR expression levels were down-regulated in the lymph node and spleen cells pointing towards receptor activation. Downstream events included a decrease in PI3K and STAT-1 and proliferation inhibition of IRPB auto-reactive T cells ex vivo. Inhibition of
interleukin-2,
tumor necrosis factor-α (TNF-α) and
interferon-γ (IFN-γ) production and up-regulation of
interleukin-10 was found in cultured splenocytes derived from CF101-treated animals. Overall, the present study data point towards a marked anti-inflammatory effect of
CF101 in EAU and support further exploration of this small molecule
drug for the treatment of
uveitis.