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Y De Kozak, M-C Naud, A Delanoye, B Thillaye-Goldenberg, C Auriault, M Wood, C Verwaerde; Ocular Transfer of Retinal Muller Cells (RMG) Tramsdiced In Vitro with Adenovirus Expressing Viral IL-10 (Ad-vIL-10) and/or CTLA-4Ig (Ad-CTLA4-Ig) Inhibits Experimental Autoimmune Uveoretinitis (EAU) . Invest. Ophthalmol. Vis. Sci. 2002;43(13):1949.
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Purpose: We have previously reported that subconjunctival or retrobulbar injection of Ad-vIL-10 performed in rodents determined a reduction of EAU. Besides, blockade of CD28-B7 interactions by soluble CTLA4-Ig fusion protein has been shown to ameliorate several autoimmune diseases including EAU. Our purpose was to improve the expression of the transgene in the eye and its effect on EAU by injecting into the vitreous either free recombinant Ad-vIL-10 or RMG cells infected in vitro with Ad-vIL-10 (RMG-vIL-10) and/or RMG infected in vitro with Ad-CTLA-4Ig (RMG-CTLA-4Ig). Methods: RMG cells were purified from normal Lewis rat retina. Free Ad-vIL-10 (1x109 pfu in 10ul) or RMG-vIL-10 and/or RMG-CTLA4-Ig (1.5-3x105 cells in 10ul) were injected into the vitreous of Lewis rats. Eyes were taken at 3, 7 and 13 days to evaluate the expression of vIL-10 mRNA by RT-PCR. Intravitreal injection of RMG-vIL-10 was performed the day of S-antigen footpad immunization or 10 days later. Histopathology, Ag-specific ear skin tests, lymphocyte proliferation and cytokine titration were performed 21 days after immunization. Results: Unilateral injection of free Ad-vIL-10 resulted in a reduced EAU (36% inhibition) only in the treated eye demonstrating a local origin of the beneficial effect. High levels of vIL-10 mRNA expression were detected in ocular tissues up to 13 days after RMG-vIL-10 ocular injection whereas no vIL-10 was detectable in the sera. The injection of RMG-Ad-vIL-10 simultaneously with or 10 days after immunization induced an inhibition of EAU (respectively 31% and 22%); the injection of RMG-CTLA4-Ig induced 39% suppression of EAU. Interestingly, co-administration of RMG-vIL-10+RMG-CTLA4-Ig resulted in an enhanced inhibition of the disease (47%). No effect on the systemic immune response was observed in treated rats. Conclusion: The efficiency of local gene delivery of vIL-10+CTLA4-Ig by RMG cells may suggest a valuable therapeutic potential for this gene transfer strategy in uveitis.
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