Therapeutic Dosing of Fingolimod (FTY720) Prevents Cell Infiltration, Rapidly Suppresses Ocular Inflammation, and Maintains the Blood-Ocular Barrier

Abstract

Fingolimod (FTY720) is an FDA-approved therapeutic drug with efficacy demonstrated in experimental models of multiple sclerosis and in phase III human multiple sclerosis trials. Fingolimod prevents T-cell migration to inflammatory sites by decreasing expression of the sphingosine-1 phosphate receptor normally required for egress from secondary lymphoid tissue. As a preclinical model of human uveitis, experimental autoimmune uveoretinitis permits assessment of immunotherapeutic efficacy. Murine experimental autoimmune uveoretinitis is induced by activation of retinal antigen-specific CD4(+) T cells that infiltrate the eye. High-dose fingolimod treatment administered before disease onset reduces ocular infiltration within hours of administration and suppresses clinicopathologic expression of experimental autoimmune uveoretinitis. In the present investigation of the efficacy of fingolimod treatment for established disease, single-dose treatment was effective and immunosuppressive ability was maintained through a dose range, demonstrating significant and rapid reduction in CD4(+) cell infiltration at clinically relevant therapeutic doses of fingolimod. A repeated-treatment regimen using a dose similar to that in current multiple sclerosis patient protocols significantly reduced infiltration within 24 hours of administration; importantly, repeated doses did not compromise the vascular integrity of the blood-ocular barrier. On withdrawal of fingolimod, drug-induced remission was lost and recrudescence of clinical disease was observed. These results support a strong therapeutic potential for fingolimod as an acute rescue therapy for the treatment of ocular immune-mediated inflammation.

An anti-TNF-α antibody mimetic to treat ocular inflammation

“…As in previous pre-clinical studies, we then utilised the highly susceptible B10.RIII mouse strain in which the immunising regimen produces consistent moderate disease severity22. Using topical endoscopic fundal imaging (TEFI)2324, clinical changes which correlate with significant inflammatory cell tissue infiltrate are evident from around day 10 post immunization.…”

FTY720 Attenuates Retinal Inflammation and Protects Blood–Retinal Barrier in Diabetic Rats

“…This dosing regimen has been reported to effectively inhibit retinal inflammation and restore vascular integrity. 33 To determine the effect of FTY720 on DR (DMþ FTY720 group, n ¼ 40), age-matched normal rats were used as normal controls (control group, n ¼ 40) and diabetic rats were used as model controls (DM group, n ¼ 40).…”

“…Evans blue (EB) leakage was performed as previously described, 33 with minor modification. Briefly, EB (20 mg/mL in saline; Sigma-Aldrich Corp.) was injected through the tail vein at a dose of 45 mg/kg.…”

A novel pathogenic RBP‐3 peptide reveals epitope spreading in persistent experimental autoimmune uveoretinitis

“…15 and has been previously published. 16 Scoring was carried out independently by trained assessors for whom the origin of the data was masked.…”

“…Human RBP-3 [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] Peptide (GPTHLFQPSLVLDMAKV LLD) and chicken ovalbumin (OVA) (ISQAVHAAHAEIN EAGR) were synthesized by Sigma-Aldrich (Poole, UK).…”