title: Inducible adeno-associated virus-mediated IL-2 gene therapy prevents autoimmune diabetes.
abstract: IL-2 and TGF-β1 play key roles in the immunobiology of Foxp3-expressing CD25(+)CD4(+) T cells (Foxp3(+)Treg). Administration of these cytokines offers an appealing approach to manipulate the Foxp3(+)Treg pool and treat T cell-mediated autoimmunity such as type 1 diabetes. However, efficacy of cytokine treatment is dependent on the mode of application, and the potent pleiotropic effects of cytokines like IL-2 may lead to severe side effects. In the current study, we used a gene therapy-based approach to assess the efficacy of recombinant adeno-associated virus vectors expressing inducible IL-2 or TGF-β1 transgenes to suppress ongoing β cell autoimmunity in NOD mice. Intramuscular vaccination of recombinant adeno-associated virus to 10-wk-old NOD female mice and a subsequent 3 wk induction of IL-2 was sufficient to prevent diabetes and block the progression of insulitis. Protection correlated with an increased frequency of Foxp3(+)Treg in the periphery as well as in the draining pancreatic lymph nodes and islets. IL-2 induced a shift in the ratio favoring Foxp3(+)Treg versus IFN-γ-expressing T cells infiltrating the islets. Induction of IL-2 had no systemic effect on the frequency or activational status of T cells and NK cells. Induction of TGF-β1 had no effect on the Foxp3(+)Treg pool or the progression of β cell autoimmunity despite induced systemic levels of activated TGF-β1 that were comparable to IL-2. These results demonstrate that inducible IL-2 gene therapy is an effective and safe approach to manipulate Foxp3(+)Treg and suppress T cell-mediated autoimmunity and that under the conditions employed, IL-2 is more potent than TGF-β1.
authors.affiliation: Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Kevin S
authors.initials: KS
authors.lastname: Goudy
authors.forename: Mark C
authors.initials: MC
authors.lastname: Johnson
authors.forename: Alaina
authors.initials: A
authors.lastname: Garland
authors.forename: Chengwen
authors.initials: C
authors.lastname: Li
authors.forename: R Jude
authors.initials: RJ
authors.lastname: Samulski
authors.forename: Bo
authors.initials: B
authors.lastname: Wang
authors.forename: Roland
authors.initials: R
authors.lastname: Tisch
mesh_terms: D000818:Animals; D000229:Dependovirus / Q000235:genetics*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology* / Q000517:prevention & control; D005260:Female; D005818:Genetic Engineering / Q000379:methods; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000276:immunology / Q000627:therapeutic use; D057809:HEK293 Cells; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D010322:Parvoviridae Infections / Q000235:genetics / Q000276:immunology / Q000517:prevention & control; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis / Q000235:genetics; D019076:Transgenes
chemical_list: D007376:Interleukin-2; D053773:Transforming Growth Factor beta1