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Modulation of autoimmune disease in the MRL-lpr/lpr mouse by IL-2 and TGF-ß1 gene therapy using attenuated Salmonella typhimurium as gene carrier

Department of Immunology, University of Glasgow, Western Infirmary, Glasgow, Scotland; Department of Clinical Laboratory Sciences, University Hospital, Queen's Medical Centre, Nottingham NG7 2UH, UK

F-P Huang

D Xu

Department of Immunology, University of Glasgow, Western Infirmary, Glasgow, Scotland

G Lindop

Department of Pathology, University of Glasgow, Western Infirmary, Glasgow, Scotland

D I Stott

Department of Immunology, University of Glasgow, Western Infirmary, Glasgow, Scotland

We have investigated the effects of interleukin-2 (IL-2) and transforming growth factor-b (TGF-b) gene therapy on the progress of autoimmune disease in MRL-lpr/lpr mice, a murine model of systemic lupus erythematosus (SLE). These mice have uncontrolled proliferation of T cells, an impaired response to T cell mitogen and produce autoantibodies against nuclear antigens, including DNA. Immune complexes formed by these autoantibodies are believed to cause glomerulonephritis and vasculitis in lupus mice and human SLE. Since there is an imbalance of cytokine production in both SLE patients and lupus mice, we examined the effects of cytokine gene therapy on the progression of autoimmune disease in MRL-lpr/lpr mice. The mice were treated orally with a non-pathogenic strain of Salmonella typhimurium bearing the aroA^-aroD^- mutations and carrying the murine genes encoding IL-2 and TGF-b. The bacteria synthesise and slowly release the cytokines in vivo. Our results show that, contrary to expectation, TGF-b gene therapy produced no improvement in pathology and generally had opposite effects to those of IL-2. IL-2 gene therapy restored the defective T cell proliferative response to mitogen and suppressed the autoantibody response, glomerulonephritis and growth of lymphoid tumours.

Key Words: SLE • IL-2 • TGF-ß • MRL-lpr/lpr • Salmonella typhimurium • gene therapy

Lupus, Vol. 8, No. 1, 29-38 (1999)
DOI: 10.1191/096120399678847308


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