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L M Hoffman, A M Maguire, J Bennett; Cell-mediated immune response and stability of intraocular transgene expression after adenovirus-mediated delivery.. Invest. Ophthalmol. Vis. Sci. 1997;38(11):2224-2233.
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PURPOSE: To evaluate the role of cell-mediated immunity in the stability of ocular adenovirus-mediated transgene expression. METHODS: Adenovirus (4 x 10(6) pfu) containing lacZ (Ad.CMVlacZ) was injected intravitreally or subretinally into one or both eyes of immunocompetent (+/+) and immunocompromised (nu/nu) CD-1 mice. Control eyes received injections of saline. Additional +/+ mice received subretinal injections of Ad.CMVlacZ with coadministration of 200 microg of human immunoglobulin (Ig) G or CTLA4Ig by intraperitoneal, intravitreal, or subretinal injection. The mice were killed at various times after injection, and their eyes were examined histologically and immunohistochemically. RESULTS: LacZ expression was extended from 1 week to more than 5 weeks in the corneal endothelium, iris, and trabecular meshwork of nu/nu mice compared with time of expression in +/+ mice when adenovirus was administered intravitreally. In contrast, subretinal injection resulted in only a minimal increase in transgene stability in nu/nu mice compared with that in +/+ mice. Neither systemic nor intraocular administration of IgG or CTLA4Ig affected the stability of lacZ expression in the retina or retinal pigment epithelium after subretinal injection in +/+ mice. Immunoglobulin G and CTLA4Ig enhanced the stability of transgene expression in the trabecular meshwork. CONCLUSIONS: A T-cell-mediated immune response appears to play a role in the loss of adenovirus-mediated lacZ expression after intravitreal but not after subretinal injection. This result implies that the subretinal space is an immune-privileged site and a favorable site for gene transfer.
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