Local Adeno-Associated Virus-Mediated Interleukin 10 Gene Transfer Has Disease-Modifying Effects in a Murine Model of Sjögren's Syndrome

Marc R. Kok, Seichii Yamano, Beatrijs M. Lodde, Jianghua Wang, Ross I. Couwenhoven, Shoshana Yakar, Antony Voutetakis, Derek Leroith, Michael Schmidt, Sandra Afione, Stanley R. Pillemer, Marjorie T. Tsutsui, Paul P. Tak, John A. Chiorini, Bruce J. Baum

Research output: Contribution to journalArticle

Abstract

Female nonobese diabetic (NOD) mice develop spontaneous autoimmune sialadenitis and loss of salivary flow, and are a widely used model of Sjögren's syndrome. We examined the feasibility of local salivary gland immunomodulatory gene delivery to alter these sequelae in NOD mice. We constructed recombinant adeno-associated virus (rAAV) vectors encoding either human interleukin 10 (rAAVhIL-10) or β-galactosidase (rAAVLacZ, control vector). Mice received rAAVhIL-10 or rAAVLacZ by retrograde submandibular ductal instillation either at age 8 weeks (early, before onset of sialadenitis), or at 16 weeks (late, after onset of sialadenitis). As a systemic treatment control, separate mice received intramuscular delivery of rAAVhIL-10 at each time point. Both submandibular and intramuscular delivery of vector led to low circulating levels of hIL-10. After submandibular administration of rAAVhIL-10, salivary flow rates at 20 weeks for both the early and late treatment groups were significantly higher than for both rAAVLacZ-administered and untreated mice. Systemic delivery of rAAVhIL-10 led to improved salivary flow in the late treatment group. Inflammatory infiltrates in submandibular glands, however, were significantly reduced only in mice receiving rAAVhIL-10 locally in the salivary gland compared with mice receiving this vector intramuscularly, or rAAVLacZ or no treatment. In addition, after submandibular rAAVhIL-10 delivery, NOD mice exhibited significantly lower blood glucose, and higher serum insulin, levels than all other groups, indicating some systemic benefit of this treatment. These studies show that expression of hIL-10 by rAAV vectors can have disease-modifying effects in the salivary glands of NOD mice, and suggest that local immunomodulatory gene transfer may be useful for managing the salivary gland pathology in Sjögren's syndrome.

Original languageEnglish (US)
Pages (from-to)1605-1618
Number of pages14
JournalHuman Gene Therapy
Volume14
Issue number17
DOIs
StatePublished - Nov 20 2003

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

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    Kok, M. R., Yamano, S., Lodde, B. M., Wang, J., Couwenhoven, R. I., Yakar, S., Voutetakis, A., Leroith, D., Schmidt, M., Afione, S., Pillemer, S. R., Tsutsui, M. T., Tak, P. P., Chiorini, J. A., & Baum, B. J. (2003). Local Adeno-Associated Virus-Mediated Interleukin 10 Gene Transfer Has Disease-Modifying Effects in a Murine Model of Sjögren's Syndrome. Human Gene Therapy, 14(17), 1605-1618. https://doi.org/10.1089/104303403322542257