Treatment of chronic sialadenitis in a murine model of Sjögren's syndrome by local fasL gene transfer.

Abstract

Infection of Fas (Fas/CD95)-mutant C57BL/6 (B6)-lpr/lpr mice with murine cytomegalovirus (MCMV) leads to a chronic sialadenitis similar to that of Sjögren's syndrome (SS). The aim of this study was to evaluate whether chronic sialadenitis would also occur in Fas ligand (FasL/CD95L)-mutant B6-gld/gld mice upon infection with MCMV and whether the expression of FasL by local gene transfer using recombinant adenoviral vectors would be an effective therapeutic strategy. B6-gld/gld mice were infected intraperitoneally with MCMV, and salivary glands were analyzed histologically at different time points. For treatment of sialadenitis, recombinant adenoviral vectors expressing the fasL gene (AdLoxpFasL + AxCANCre) or the lacZ gene (AdCMVLacZ) were locally injected into the salivary glands of MCMV-infected B6-gld/gld mice and uninfected B6-+/+ and B6-gld/gld mice. Following MCMV infection, B6-gld/gld mice developed an acute and chronic sialadenitis characterized by multiple foci of infiltrating T cells. After local injection of adenoviral vectors, high levels of lacZ or fasL gene expression could be detected in acinar and ductal cells. Treatment of acute and chronic sialadenitis in B6-gld/gld mice with local fasL gene transfer resulted in a significant reduction in the number of inflammatory foci and tissue destruction in salivary glands compared with mice treated with AdCMVLacZ. Despite high levels of FasL expression after injection of recombinant vectors, <5% of ductal and acinar cells were TUNEL positive, demonstrating that, in this model of SS, acinar and ductal cells were not highly sensitive to FasL-mediated apoptosis. Chronic sialadenitis similar to that of SS developed in B6-gld/gld mice after MCMV infection. FasL expression was reconstituted by local gene transfer, resulting in significant reduction of infiltrating mononuclear cells, which indicates that local gene transfer of fasL might be a novel treatment for chronic sialadenitis.