Anti-Inflammatory Effects of Clarstatin, a Shared-Epitope–Antagonistic Cyclic Peptide, on Experimental Autoimmune Uveitis in Mice

PURPOSE. Polymorphism and mutations of human leukocyte antigens (HLAs) and calreticulin are risk factors for uveitis. Here, we sought to determine the therapeutic effects of Clarstatin, a cyclic peptide antagonist of the HLA shared-epitope–calreticulin interaction, in experimental autoimmune uveitis (EAU) models. METHODS. Mice were injected with Clarstatin intraperitoneally and its effect was compared to that of corticosteroid. EAU was evaluated clinically and histologically. Ocular infiltration of CD45⁺ hematopoietic cells and splenocyte CD4⁺ expression were determined using immunofluorescence and flow cytometry (fluorescence-activated cell sorting [FACS]). ELISA was used to measure the ocular level of the proinflammatory cytokines. RESULTS. Clarstatin significantly ameliorated the severity of EAU in the C57BL/6J mild and the B10.RIII severe mice models. There was a significant dose and time-dependent decrease, in the range of 30% to 80%, in the clinical score (P < 0.05), histological score (P < 0.05), and number of retinal and spleen CD45⁺ cells (P < 0.05 and P < 0.001, respectively), a comparable effect to corticosteroid. Clarstatin reduced the intraocular levels of interleukin 6 (IL-6; P < 0.05) and monocyte chemoattractant protein-1 (MCP-1; P < 0.01) by 41% and 59%, respectively. CONCLUSIONS. Systemic delivery of Clarstatin significantly improved mild and severe EAU. Its potential anti-inflammatory therapeutic effects represent a novel mode of treatment in ocular inflammation. It may also be a relevant treatment modality in systemic autoimmune conditions in which calreticulin plays a role in their pathogenesis.