LX211 (Voclosporin) Suppresses Experimental Uveitis and Inhibits Human T Cells

• Published in: Investigative ophthalmology & visual science 2009-01, Vol.50 (1), p.249-255
• Main Authors: Cunningham, Matthew A, Austin, Bobbie Ann, Li, Zhuqing, Liu, Baoying, Yeh, Steven, Chan, Chi-Chao, Anglade, Eddy, Velagaleti, Poonam, Nussenblatt, Robert B
• Format: Article
• Language: English
• Subjects: Animals; Autoimmune Diseases - chemically induced; Autoimmune Diseases - immunology; Autoimmune Diseases - prevention & control; Biological and medical sciences; Cyclosporine - pharmacology; Cytokines - metabolism; Disease Models, Animal; Eye and associated structures. Visual pathways and centers. Vision; Eye Proteins; Fundamental and applied biological sciences. Psychology; Humans; Immunosuppressive Agents - pharmacology; Injections, Subcutaneous; Lymphocyte Activation - drug effects; Male; Medical sciences; Ophthalmology; Rats; Rats, Inbred Lew; Retinitis - chemically induced; Retinitis - immunology; Retinitis - prevention & control; Retinol-Binding Proteins; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; Treatment Outcome; Uvea diseases; Uveitis - chemically induced; Uveitis - immunology; Uveitis - prevention & control; Vertebrates: nervous system and sense organs
• ISSN: 0146-0404; 1552-5783; 1552-5783
• DOI: 10.1167/iovs.08-1891

To test the therapeutic effectiveness of voclosporin against experimental autoimmune uveoretinitis (EAU) in rats and to evaluate its effect on human T cells. EAU was induced by immunization with a uveitogenic protein. Voclosporin administration, by subcutaneous injection, began on day (d) 0 or d7 after immunization. Treatment effectiveness was evaluated in vivo using clinical EAU scoring (d7-d13) and histopathologic evaluation of enucleated eyes after experimental termination. Rodent lymphocytes were harvested from lymph nodes on d14 for antigen-specific proliferation assays. The effect of voclosporin on human T-cell proliferation and cytokine secretion was examined in vitro. Voclosporin prevented EAU development in rats receiving medium and high preventive doses, whereas high-dose voclosporin administration effectively treated EAU. Lymphocytes from animals treated with voclosporin had decreased antigen-specific proliferation in vitro compared with lymphocytes from untreated animals. No evidence of abnormal ocular histopathology was found in the eyes from animals that received high doses of therapeutic voclosporin. Using human T cells, voclosporin inhibited human T-cell proliferation up to 100-fold. Furthermore, voclosporin treatment of human T cells significantly reduced pan T-cell effector responses. Voclosporin effectively suppressed uveoretinitis in an animal model that imitates the human inflammatory ocular disease by inhibiting lymphocyte proliferation. In addition, voclosporin effectively inhibited human T-cell proliferation and function in vitro. The authors report the first evidence supporting the application of voclosporin to treat intraocular inflammation.