Systemic Overexpression of IL-10 Induces CD4+CD25+ Cell Populations In Vivo and Ameliorates Type 1 Diabetes in Nonobese Diabetic Mice in a Dose-Dependent Fashion

• Published in: The Journal of immunology (1950) 2003-09, Vol.171 (5), p.2270-2278
• Main Authors: Goudy, Kevin S, Burkhardt, Brant R, Wasserfall, Clive, Song, Sihong, Campbell-Thompson, Martha L, Brusko, Todd, Powers, Matthew A, Clare-Salzler, Michael J, Sobel, Eric S, Ellis, Tamir M, Flotte, Terence R, Atkinson, Mark A
• Format: Article
• Language: English
• Subjects: Adenoviridae - genetics; Animals; Antibody Formation - genetics; Autoantibodies - biosynthesis; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; Dependovirus - genetics; Diabetes Mellitus, Type 1 - genetics; Diabetes Mellitus, Type 1 - immunology; Diabetes Mellitus, Type 1 - pathology; Diabetes Mellitus, Type 1 - prevention & control; Dose-Response Relationship, Immunologic; Female; Genetic Therapy - methods; Genetic Vectors; Immunity, Cellular - genetics; Injections, Intramuscular; Insulin Antibodies - biosynthesis; Interleukin-10 - biosynthesis; Interleukin-10 - genetics; Interleukin-10 - therapeutic use; Islets of Langerhans - immunology; Islets of Langerhans - pathology; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Receptors, Interleukin-2 - biosynthesis; Recombination, Genetic; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; Time Factors
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.171.5.2270

Early systemic treatment of nonobese diabetic mice with high doses of recombinant adeno-associated virus (rAAV) vector expressing murine IL-10 prevents type 1 diabetes. To determine the therapeutic parameters and immunological mechanisms underlying this observation, female nonobese diabetic mice at 4, 8, and 12 wk of age were given a single i.m. injection of rAAV-murine IL-10 (10(4), 10(6), 10(8), and 10(9) infectious units (IU)), rAAV-vector expressing truncated murine IL-10 fragment (10(9) IU), or saline. Transduction with rAAV-IL-10 at 10(9) IU completely prevented diabetes in all animals injected at all time points, including, surprisingly, 12-wk-old animals. Treatment with 10(8) IU provided no protection in the 12-wk-old injected mice, partial prevention in 8-wk-old mice, and full protection in all animals injected at 4 wk of age. All other treatment groups developed diabetes at a similar rate. The rAAV-IL-10 therapy attenuated pancreatic insulitis, decreased MHC II expression on CD11b+ cells, increased the population of CD11b+ cells, and modulated insulin autoantibody production. Interestingly, rAAV-IL-10 therapy dramatically increased the percentage of CD4+CD25+ regulatory T cells. Adoptive transfer studies suggest that rAAV-IL-10 treatment alters the capacity of splenocytes to impart type 1 diabetes in recipient animals. This study indicates the potential for immunomodulatory gene therapy to prevent autoimmune diseases, including type 1 diabetes, and implicates IL-10 as a molecule capable of increasing the percentages of regulatory cells in vivo.