title: Inhibition of experimental auto-immune uveitis by the A3 adenosine receptor agonist CF101.
abstract: 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.
authors: Can-Fite BioPharma, Petach Tikva, Israel.
authors: Sara
authors: S
authors: Bar-Yehuda
authors: Dror
authors: D
authors: Luger
authors: Avivit
authors: A
authors: Ochaion
authors: Shira
authors: S
authors: Cohen
authors: Renana
authors: R
authors: Patokaa
authors: Galina
authors: G
authors: Zozulya
authors: Phyllis B
authors: PB
authors: Silver
authors: Jose Maria Garcia Ruiz
authors: JM
authors: de Morales
authors: Rachel R
authors: RR
authors: Caspi
authors: Pnina
authors: P
authors: Fishman
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D058909:Adenosine A3 Receptor Agonists / Q000627:therapeutic use*; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016753:Interleukin-10 / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D008198:Lymph Nodes / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D043684:Receptor, Adenosine A3 / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism; D013154:Spleen / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014605:Uveitis / Q000188:drug therapy* / Q000276:immunology* / Q000378:metabolism
chemical_list: D058909:Adenosine A3 Receptor Agonists; C478920:CF101; D007376:Interleukin-2; D043684:Receptor, Adenosine A3; D050794:STAT1 Transcription Factor; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D019869:Phosphatidylinositol 3-Kinases; D000241:Adenosine