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Jianping Gao, Reuben Sana, Virginia L. Calder, Larry A. Wheeler, Michael E. Stern; Evaluation of Effects of Cyclosporine in a Rat Model of Experimental Autoimmune Anterior Uveitis (EAAU). Invest. Ophthalmol. Vis. Sci. 2011;52(14):2284.
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To determine if cyclosporin A (CsA) is effective in attenuating immune-based inflammation in a rat EAAU model.
EAAU was induced in Lewis rats by a hind-footpad injection using melanin-associated antigen (MAA, 150µg/rat). Animals were randomized into 3 groups (n=6), and treated with CsA (10mg/kg, qd) intraperitoneally (ip), Restasis (0.05% CsA, tid, Allergan) topically, or saline (ip). Clinical examination was performed using Slit lamp biomicroscopy at Day 7, 11, 14, 19 and 25 post-immunization. Leukocytes from spleen were analyzed using flow cytometry for MHC class II and CCR2 expressions to determine the immune activation status via disease progression. Aqueous humors (AH) were harvested to determine leukocyte cell numbers and differentiation, protein exudation, and proinflammatory cytokine/chemokine concentrations using bioassays or Luminex analysis.
In the saline-treated animals, (1) intraocular inflammation was first detected at day 11, became progressively severe and peaked at day 19; (2) MHC class II expressions were upregulated primarily on the splenic CD4+ T cells and CD11b/c+ macrophages over EAAU disease progression, and remained at a high level at day 25; (3) CD4+ T cells were the major leukocyte population infiltrated in the anterior chamber; and (4) the levels of IL-2, IL-17, IL-1β, MCP-1 and RANTES were markedly increased in the AH. When given systemically, CsA almost completely prevented the development of EAAU disease at all measures conducted as above (≥ 92% inhibition, p<0.001). When given topically, Restasis significantly reduced the severity of EAAU at the peak of intraocular inflammation on day 19, as determined by a decrease in clinical signs, inflammatory cell counts (84% ↓, p=4.5E-05), protein exudates in AH (60% ↓, p<0.005), and the levels of IL-2 (72% ↓, p<0.011), IL-17 (74% ↓, p<0.026), IL-1β (65% ↓, p<0.013), MCP-1 (81% ↓, p<0.005), and RANTES (87% ↓, p<0.001) in AH. MHC class II expressions on splenic leukocytes were not significantly affected by topical Restasis treatment.
Systemic treatment with cyclosporine A completely inhibited the antigen MAA-driven, T cell-mediated inflammation in the rat EAAU model. Topical Restasis was also effective in attenuating intraocular inflammation in this model.
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