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David A. Copland, Volker Brinkmann, Karen Anderson, Jian Liu, Lindsay B. Nicholson, Andrew D. Dick; Different FTY720 (fingolimod) Treatment Regimens Can Suppress Autoimmune Uveoretinitis. Invest. Ophthalmol. Vis. Sci. 2011;52(14):4301.
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To determine the efficacy of a non-steroid approach to suppressing active intraocular inflammation and inducing long term disease remission. Previous experimental autoimmune uveoretinitis (EAU) studies demonstrate that a short-term high dose treatment with Fingolimod (FTY720) a sphingosine-1-phosphatase analogue prevents T-cell migration to inflammatory sites and rapidly reduces ocular infiltrate. This suggests the clinical potential to serve as a rescue therapy for active ocular inflammatory conditions. EAU serves as a preclinical model of human uveitis, and permits assessment of immunotherapeutic efficacy.
EAU was induced in B10.RIII mice by immunization with hRBP-3161-180, and disease severity determined by clinical assessment and flow cytometric analysis of retinal infiltrate. Groups of mice were treated following onset of clinical disease with a single oral dose of FTY720 or control vehicle at different concentrations (10, 1 and 0.1 mg/kg). Retinal infiltrate was examined and enumerated by flow cytometric methods, 24 hours after drug administration. In further experiments following disease onset, mice received a repetitive (X5 doses) low dose regimen of FTY720 or control (0.3mg/kg daily), with assessment of infiltrate at 24 hours after the final dose. Long-term efficacy of repeated FTY720 treatment was assessed on day 25, using histological methods to determine disease severity and vascular integrity.
Retinal infiltrate 24 hours following single dose treatment demonstrate 78% reduction of CD4+ cells in mice receiving the highest dose of FTY720 compared to control animals, and this reduction is dose dependent and significant even at the lowest dose. Mice treated from disease onset with a repetitive low dose regimen of 0.3 mg/kg FTY720 demonstrate 75% reduction in retinal infiltrate, and reduced clinical disease scores. Furthermore, the degree of macrophage and neutrophil infiltrate was also reduced by 60% and 50% respectively as compared to controls.
These results demonstrate the potential clinical benefit that FTY720 may bring to the treatment of ocular immune-mediated inflammation, as a non-steroid based rescue and maintenance therapeutic.
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