We previously showed that adeno-associated virus 2 (AAV2) mediated subretinal delivery of human interferon-alpha (IFN-alpha) could effectively inhibit experimental autoimmune uveoretinitis (EAU). In this study we investigated whether subretinal injection of both AVV2. IFN-alpha and AAV2. IL-4 had a stronger inhibition on EAU activity. B10RIII mice were subretinally injected with AAV2. IFN-alpha alone (1.5x10(7) vg), AAV2. IL-4 alone (3.55x10(7) vg), and AAV2. IFN-alpha combined with AAV2. IL-4. PBS, AAV2 vector encoding green fluorescent protein (AAV2. GFP) (5x10(7) vg) was subretinally injected as a control. IFN-alpha and IL-4 were effectively expressed in the eyes from three weeks to three months following subretinal injection of AAV2 vectors either alone or following combined administration and significantly attenuated EAU activity clinically and histopathologically. AAV2. IL-4 showed a better therapeutic effect as compared to AAV2. IFN-alpha. The combination of AAV2. IL-4 and AAV2. IFN-alpha was not significantly different as compared to AAV2. IL-4 alone. There was no difference concerning DTH (delayed-type hypersensitivity) reaction, lymphocyte proliferation and IL-17 production among the investigated treatment groups, suggesting that local retinal gene delivery did not affect the systemic immune response.