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

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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. Administration of immunoregulatory cytokines has been performed in animal models of autoimmune diseases to gain insight into the pathogenesis of disease development. In these studies, large amounts of recombinant cytokines were repeatedly administered because of their short half-lives in vivo, which sometimes lead to conflicting outcomes resulting in either exacerbation or amelioration of autoimmune diseases. Here we present an alternative approach for systemic administration of immunoregulatory cytokines to autoimmune disease models. We previously demonstrated that intramuscular plasmid injection serves as a useful method of long-term systemic delivery of cytokines by combining the strong CAG (cytomegalovirus immediate-early enhancer–chicken β-actin hybrid) promoter and bupivacaine pretreatment. We demonstrated that the incidence of autoimmune diabetes in the NOD mouse model is markedly reduced by IL-10, a cytokine with immunosuppressive properties, produced by intramuscular DNA injection of IL-10-expressing plasmid DNA. Our data suggest that cytokine delivery mediated by intramuscular plasmid DNA injection is potentially applicable to the treatment of human autoimmune diseases.