THE ROLE OF MACROPHAGES IN THE PATHOGENESIS OF HSV-1 INDUCED CHORIORETINITIS IN BALB/C MICE

Purpose. To examine the effects of modification of immune effector cells, including macrophages, in the pathogenesis of herpes simplex virus retinitis in BALB/c mice. Methods. Two intravitreal injections (2 mu l each) of anti-CD11b monoclonal antibody (mAb) [13 mu g/mu l] were administered to the contralateral eyes of 10 BALB/c mice on days 6 and 8 after HSV inoculation into the right anterior chamber (AC) with HSV-1. A control group consisted of mice injected with anti-HLA-DR mAb in the same fashion. Specific macrophage depletion was performed in an additional group of 12 BALB/c mice by intravenous (IV) injection of dichloromethylene diphosphonate (Cl(2)MDP)-liposomes 7 days before AC HSV-1 inoculation into the eye. Control group consisted of mice receiving IV PBS-liposomes. Mice were clinically observed for 14 days postinfection, and the incidence of chorioretinal disease was confirmed by histopathologic studies. Results. Intravitreal injections of anti-CD11b mAb produced a dramatic suppression of the contralateral retinal necrosis (2 of 10 mice) compared to 9 of 10 controls receiving an irrelevant antibody therapy (P < 0.05). Mice treated with IV Cl(2)MDP-liposomes also showed a significant inhibition of the development of contralateral chorioretinitis, with only 3 of 12 mice developing retinal disease compared to 9 of 12 mice from the control group (P < 0.05). FACS analysis performed on peripheral blood and spleen cells showed a significant depletion of Mac-1(+) cells of Cl(2)MDP-liposome-treated but not of PBS-liposome-treated mice (controls). Conclusion. Intravitreal anti-CD11b mAb therapy, a broadly directed depletion strategy against many effector cells (macrophages, granulocytes, natural killer cells, and even cytotoxic T-cells) was most efficient in suppressing the HSV-1 induced contralateral disease. A more Specific technique (IV Cl(2)MDP-liposome therapy) to deplete macrophages also produced a significant inhibition of HSV-1 induced contralateral chorioretinitis. These findings suggest that macrophages are important participants in the effector phase of the destructive inflammatory immune response induced by HSV-1 in the eye.