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(Investigative Ophthalmology and Visual Science. 2009;50:1761-1768.)
© 2009 by The Association for Research in Vision and Ophthalmology, Inc.
doi:10.1167/iovs.08-3027
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Local Ocular Immunomodulation Resulting from Electrotransfer of Plasmid Encoding Soluble TNF Receptors in the Ciliary Muscle

Laura Kowalczuk,1 Elodie Touchard,1 Serge Camelo,1 Marie-Christine Naud,1 Beatriz Castaneda,1 Nadege Brunel,2 Bernadette Besson-Lescure,2 Brigitte Thillaye-Goldenberg,1 Pascal Bigey,3,4 David BenEzra,1,5,6 Yvonne de Kozak,1 and Francine Behar-Cohen1,7

1From the INSERM UMRS 872 Team17, Centre de Recherches des Cordeliers, Université Pierre et Marie Curie, Université Paris Descartes, Paris, France; 2INSERM IFR65/U515, Saint Antoine Hospital, Paris, France; 3INSERM U640, CNRS UMR8151, Faculté de Pharmacie, Chemical and Genetic Pharmacology Laboratory; Université Paris-Descartes, Paris, France; 4Ecole Nationale Supérieure de Chimie de Paris, Paris, France; 5The BenEzra Eye Institute, Assouta-Rishon, Israel; the 6Department of Ophthalmology, Hadassah University Hospital, Jerusalem, Israel; and the 7Department of Ophthalmology, Hôtel-Dieu Hospital, Paris, France.

PURPOSE. Plasmid electrotransfer in the ciliary muscle allows the sustained release of therapeutic proteins within the eye. The aim of this study was to evaluate whether the ocular production of TNF-{alpha} soluble receptor, using this nonviral gene therapy method, could have a beneficial local effect in a model of experimental autoimmune uveoretinitis (EAU).

METHODS. Injection of a plasmid encoding a TNF-{alpha} p55 receptor (30 µg) in the ciliary muscle, combined with electrotransfer (200 V/cm), was carried out in Lewis rat eyes 4 days before the induction of EAU by S-antigen. Control eyes received naked plasmid electrotransfer or simple injection of the therapeutic plasmid. The disease was evaluated clinically and histologically. Cytokines and chemokines were analyzed in the ocular media by multiplex assay performed 15 and 21 days after immunization.

RESULTS. Ocular TNF-{alpha} blockade, resulting from the local secretion of soluble receptors, was associated with delayed and significantly less severe uveitis, together with a reduction of the retinal damages. Compared with the controls, treated eyes showed significantly lower levels of IL-1β and MCP1, higher levels of IL-13 and IL-4, and reduced NOS-2 expression in infiltrating cells. Treatment did not influence TNF-{alpha} levels in inguinal lymph nodes.

CONCLUSIONS. Taken together, these results indicate that local immunomodulation was achieved and that no systemic adverse effects of TNF-{alpha} blockade observed after systemic injection of TNF-{alpha} inhibitors should be expected.






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