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T. Yoshimura, O. Benny, L. Bazinet, R. J. D'Amato; Autoimmune Retinal Inflammation is Suppressed by a Novel Polymeric Anti-Angiogenic Drug. Invest. Ophthalmol. Vis. Sci. 2010;51(13):817.
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Retinal inflammation caused by non-infectious, autoimmune uveitis is one of the major causes of blindness. Lodamin, a polymeric conjugation of TNP-470 and a potent broad-spectrum anti-angiogenic drug, has been shown to inhibit angiogenesis and tumor growth by oral administration without adverse side effects. In this study, we show for the first time the anti-inflammatory effect of Lodamin on T cell proliferation/differentiation. These effects are demonstrated in a model of autoimmune retinal inflammation.
Lodamin was prepared by chemical conjugation of polyethylene glycol-polylactic acid (PEG-PLA) to TNP-470. Carboxyfluorescein succinimidyl ester (CFSE)-labeled splenocytes from C57BL/6 mice were activated with αCD3 Ab in the presence of vehicle or Lodamin. Proliferation of CD4+ T cells was measured by CFSE dilution. CD4+ T cells were differentiated into Th1 (IL-12 and αIL-4 Ab) and Th17 (TGF-β1, IL-6, and αIFN-γ/αIL-4 Ab) in the presence of vehicle or Lodamin. Expansion of Th1/Th17 cells was evaluated by intracellular cytokine staining. Experimental autoimmune uveitis (EAU) was induced by immunizing C57BL/6 mice with human interphotoreceptor retinoid-binding protein (IRBP) 1-20. Lodamin at a dose of 30mg/kg, or vehicle was orally administrated every other day after immunization. EAU severity was evaluated clinically and histopathologically on day 21. Draining lymph node cells were harvested and IRBP-specific IFN-γ/IL-17 production was analyzed by ELISA. mRNA from retinas was isolated for quantitative real-time PCR (qPCR).
Lodamin suppressed αCD3-mediated CD4+ T cell proliferation and importantly, both Th1/Th17 differentiation. Oral treatment of Lodamin significantly suppressed IRBP-specific IFN-γ/IL-17 production and EAU progression both clinically and histopathologically. Furthermore, qPCR analysis revealed that Lodamin attenuated intraocular expression of major inflammatory cytokines such as IFN-γ, IL-17, and IL-6.
The results show that Lodamin significantly suppresses T cell proliferation, Th1/Th17 differentiation, IRBP-specific Th1/Th17 responses and disease severity in EAU. We conclude that oral treatment with Lodamin holds promise for the treatment of retinal inflammatory diseases.
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