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B. A. Austin, M. A. Cunningham, Z. Li, B. Liu, C.-C. Chan, S. Yeh, E. Anglade, P. Velagalati, R. B. Nussenblatt; LX211 (ISA247) Suppresses Anti-CD3 Activated Human T-Cell Proliferation and Effectively Treats Experimental Autoimmune Uveitis in Rats. Invest. Ophthalmol. Vis. Sci. 2008;49(13):4745.
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© ARVO (1962-2015); The Authors (2016-present)
LX211, also known as ISA247, is a next generation calcineurin inhibitor that inhibits lymphocyte cell cycle progression at GO/G1. The purpose of the current study was to examine the impact of LX211 on human T-cell proliferation and cytokine secretion and to further test the therapeutic effectiveness of LX211 against experimental autoimmune uveitis (EAU) in a rat model.
T-cells were purified from human peripheral blood mononuclear cells and stimulated with anti-CD3 in the presence of vehicle, cyclosporine A (CsA: 10 or 100 nM) or LX211 (0.01, 0.1, 1, 10, and 100 nM). Cytokine secretion was evaluated on d3, while T-cell proliferation in parallel cultures was assessed at d5. For in vivo studies, EAU was induced on d0 by immunization with uveitogenic protein (IRBP). Daily subcutaneous injections of LX211 (2.5 mg/kg, 10 mg/kg, or 40 mg/kg) were delivered on d0-d13 (preventative) or d7-d13 (therapeutic). Treatment effectiveness was evaluated daily (d7-d13) using clinical EAU scoring. Upon termination of the experiment on d14, posterior ocular histopathology scores were assigned by a masked observer.
LX211 suppressed anti-CD3 activated human T-cell proliferation and TH1, TH2, and TH17 cytokine secretion. LX211 also prevented EAU development in rats receiving medium and high preventative doses, while EAU was effectively treated in rats receiving high therapeutic doses of LX211. In ocular tissue sections, evaluated in a double-masked fashion, no histopathology was found in eyes from animals, who received high LX211 therapeutic doses.
In the current study, LX211 inhibited human T-cell proliferation and reduced cytokine secretion, at a lower concentration than CsA. Our observation that LX211 more potently suppressed human T-cells than CsA is comparable to a previous report where LX211 suppressed non-human primate T-cell proliferation at a 4-fold lower dose than CsA. In this study, LX211 inhibited the production of a broad range of human T-cell cytokines, including cytokines classified as TH1, TH2, and TH17 lineage. Our group is the first to examine the effectiveness of LX211 to treat intraocular inflammation, adding to the clinical applications of the immunosuppressant LX211/ISA247.
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