CELL-MEDIATED IMMUNE-RESPONSE AND STABILITY OF INTRAOCULAR TRANSGENE EXPRESSION AFTER ADENOVIRUS-MEDIATED DELIVERY

Purpose. To evaluate the role of cell-mediated immunity in the stabili ty of ocular adenovirus-mediated transgene expression. Methods. Adenov irus (4 X 10(6) pfu) containing lacZ (Ad.CMVlacZ) was injected intravi treally or subretinally into one or both eyes of immunocompetent (+/+) and immunocompromised (nu/nu) CD-1 mice. Control eyes received inject ions of saline. Additional +/+ mice received subretinal injections of Ad.CMVlacZ with coadministration of 200 mu g of human immunoglobulin ( Ig) G or CTLA4Ig by intraperitoneal, intravitreal, or subretinal injec tion. 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 compa red with time of expression in +/+ mice when adenovirus was administer ed 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 I gG 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 expre ssion in the trabecular meshwork. Conclusions. A T-cell-mediated immun e response appears to play a role in the loss of adenovirus-mediated l acZ 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.