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.
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.
Goudy
Kevin S
KS
Department of Pathology, Powell Gene Therapy Center, University of Florida, 1600 SW Archer Road, Gainesville, FL 32610, USA.
Burkhardt
Brant R
BR
Wasserfall
Clive
C
Song
Sihong
S
Campbell-Thompson
Martha L
ML
Brusko
Todd
T
Powers
Matthew A
MA
Clare-Salzler
Michael J
MJ
Sobel
Eric S
ES
Ellis
Tamir M
TM
Flotte
Terence R
TR
Atkinson
Mark A
MA
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000917:Antibody Formation / Q000235:genetics; D001323:Autoantibodies / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D007111:Immunity, Cellular / Q000235:genetics; D007273:Injections, Intramuscular; D007330:Insulin Antibodies / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis / Q000235:genetics* / Q000627:therapeutic use*; D007515:Islets of Langerhans / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis*; D011995:Recombination, Genetic; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D013997:Time Factors
D001323:Autoantibodies; D007330:Insulin Antibodies; D015375:Receptors, Interleukin-2; D016753:Interleukin-10