Systemic Delivery of Interleukin 10 by Intramuscular Injection of Expression Plasmid DNA Prevents Autoimmune Diabetes in Nonobese Diabetic Mice

Abstract

We previously demonstrated that intramuscular plasmid injection serves as a useful method of long-term systemic delivery of cytokines. In the present study, we assess intramuscular DNA injection as a means of systemically delivering interleukin 10 (IL-10), a cytokine with immunosuppressive properties, and preventing the progression of autoimmune diabetes in the nonobese diabetic (NOD) mouse, an excellent model for human insulin-dependent diabetes mellitus (IDDM). We injected IL-10 expression plasmid (pCAGGS-IL10) or a control pCAGGS plasmid into the muscles of NOD mice twice at 3 and 5 weeks of age. IL-10 was detectable by ELISA in the sera of mice injected with pCAGGS-IL10 for more than 2 weeks after the injection. Although the severity of insulitis at 13 weeks of age was not improved by the intramuscular injection of pCAGGS-IL10, the incidence of diabetes was markedly reduced in NOD mice injected with pCAGGS-IL10 as compared with those injected with pCAGGS or as compared with nontreated NOD mice. These results show that the progression of autoimmune diseases in mice can effectively be suppressed by intramuscular DNA injection, and suggest that this method is potentially applicable to the treatment of human autoimmune diseases.

Treatment of severe hypercholesterolemia in apolipoprotein E-deficient mice by intramuscular injection of plasmid DNA

“…11,[16][17][18][19][20][21] Plasmid DNA delivered directly to muscle generally results in persistent albeit low-level gene expression since skeletal muscle takes up, episomally maintains and expresses plasmid DNA for a time notably longer than other tissues. 12,25,[40][41][42] Furthermore, this method of gene delivery circumvents some of the problems encountered with viral vectors.…”

“…15 Nevertheless, secretion in blood plasma and/or systemic biological activity of the transgene have been confirmed after i.m. delivery of plasmid vectors encoding for erythropoietin, 16 factor VII, 17 rat kallikrein-binding protein (RKBP), 18 vascular endothelial growth factor (VEGF), 19 interleukin 10, 20 and interferon-␥ receptor/IgG1 fusion protein. 21 These studies suggest that i.m.…”

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

“…For example, early systemic treatment with exogenous murine IL-10 can inhibit type 1 diabetes in NOD mice, while, in contrast, local expression (intraislet) accelerates the onset of disease (17)(18)(19)(20)(21)(22). In addition, aberrations in IL-10 levels or function have been associated with type 1 diabetes in both humans and NOD mice (22,23).…”

CXCL10 DNA Vaccination Prevents Spontaneous Diabetes through Enhanced β Cell Proliferation in NOD Mice

“…A plasmid DNA injection system is used for delivery of gene products themselves or for eliciting an immune response against gene products depending on the nature of the selected plasmid (34). Although we have used pCAGGS-murine cytokine DNA treatment to deliver a cytokine itself systemically, the "immune response" against produced cytokines had never been observed in our previous studies (30,35,36). Therefore, we decided to use rat instead of murine CXCL10 cDNA, in the expectation of eliciting a vaccination-like effect because the overall identity of rat CXCL10 to murine CXCL10 is ϳ80% at the amino acid level, and we have already obtained a mouse CXCL10-neutralizing Ab by immunization of rat CXCL10 (10).…”