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Simultaneous stimulation of Fas-mediated apoptosis and blockade of costimulation prevent autoimmune diabetes in mice induced by multiple low-dose streptozotocin

Gene Therapy volume 11, pages 982–991 (2004)Cite this article

Abstract

Type I diabetes is the result of a selective destruction of insulin-producing β cells in pancreatic islets by autoreactive T cells. Depletion of autoreactive T cells through apoptosis may be a potential strategy for the prevention of autoimmune diabetes. Simultaneous stimulation of the Fas-mediated pathway and blockade of costimulation by a CTLA4-Fas ligand (FasL) fusion protein has been reported to lead to enhanced in vitro apoptosis of peripheral lymphocytes. To test the feasibility of CTLA4-FasL-based gene therapy to prevent autoimmune diabetes, we developed a recombinant adenovirus containing the human CTLA4-FasL gene (AdCTLA4-FasL). A single injection of 2 × 108 plaque-forming units of AdCTLA4-FasL via the tail vein of mice greatly reduced the incidence of autoimmune diabetes (13%, n=15) induced by multiple low-dose streptozotocin. AdCTLA4-FasL administration abrogated pancreatic insulitis, significantly increased apoptosis of pancreatic T-lymphocytes, and altered splenocyte response to mitogenic and antigenic stimulation. These results indicate the therapeutic potential of simultaneous stimulation of the Fas-mediated pathway and blockade of costimulation by adenovirus-mediated CTLA4-FasL gene transfer in the prevention of autoimmune diabetes.

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Acknowledgements

This work was supported by a grant, 39830340, from the National Natural Science Foundation of China. We wish to express our gratitude to S Nagata of the Osaka University Medical School, JF Elliott of the University of Alberta, Canada, and Tong-chuan He of the Howard Hughes Medical Institute for their gifts.

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  1. Y Jin and A Qu: These authors contributed equally to this paper

Authors and Affiliations

  1. Department of Immunology, Peking University Health Science Center, Beijing, People's Republic of China

    Y Jin, G M Wang, J Hao, X Gao & S Xie

  2. Department of Physiology, Peking University Health Science Center, Beijing, People's Republic of China

    A Qu

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Jin, Y., Qu, A., Wang, G. et al. Simultaneous stimulation of Fas-mediated apoptosis and blockade of costimulation prevent autoimmune diabetes in mice induced by multiple low-dose streptozotocin. Gene Ther 11, 982–991 (2004). https://doi.org/10.1038/sj.gt.3302260

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