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  • Title: Prevention and reversal of lupus in NZB/NZW mice by costimulatory blockade with adeno-associated virus-mediated gene transfer.
    Author: Ye X, Zhu T, Bastacky S, McHale T, Li J, Xiao X.
    Journal: Arthritis Rheum; 2005 Dec; 52(12):3975-86. PubMed ID: 16329128.
    Abstract:
    OBJECTIVE: To investigate the potency of costimulatory blockade with adeno-associated virus (AAV)-mediated gene transfer in the prevention and reversal of lupus in a murine model. METHODS: AAV vectors expressing CTLA-4Ig or CD40Ig were injected into NZB/NZW mice. Serum levels of transgene expression and autoantibody titers were determined by enzyme-linked immunosorbent assay. The therapeutic effects on proteinuria, renal pathologic features, and survival rate were evaluated. Splenic T cell phenotypes were analyzed by flow cytometry. The humoral immune response to a foreign antigen was also examined in treated mice. RESULTS: A single injection of AAV serotype 8 (AAV8)-CTLA-4Ig in neonatal NZB/NZW mice before the onset of lupus effectively delayed and inhibited autoantibody production, proteinuria, and kidney damage and prolonged their lifespan. In addition, coinjection of AAV8-CTLA-4Ig and AAV8-CD40Ig vectors into neonatal mice achieved a synergistic effect and the best efficacy. The preventive effects were attributed to suppression of CD4+ T cell activation and the transition from naive to memory T cells. Moreover, coinjection of these 2 vectors in adult mice reversed the existing autoantibody levels, suppressed the development of proteinuria, and prolonged their lifespan. The therapeutic effects were found to be dependent on the vector dose. In addition, AAV-mediated long-term gene expression did not severely suppress the host humoral response to foreign antigen. CONCLUSION: Our findings show that delivery of costimulatory inhibitor transgenes by AAV vectors could prevent and reverse lupus in this murine model, suggesting the potential of AAV-mediated gene transfer as an alternative treatment for lupus.
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