title: β-cell-specific IL-35 therapy suppresses ongoing autoimmune diabetes in NOD mice.
abstract: IL-35 is a recently identified cytokine exhibiting potent immunosuppressive properties. The therapeutic potential and effects of IL-35 on pathogenic T effector cells (Teff) and Foxp3+Treg, however, are ill defined. We tested the capacity of IL-35 to suppress ongoing autoimmunity in NOD mice. For this purpose, an adeno-associated virus vector in which IL-35 transgene expression is selectively targeted to β cells via an insulin promoter (AAV8mIP-IL35) was used. AAV8mIP-IL35 vaccination of NOD mice at a late preclinical stage of type 1 diabetes (T1D) suppressed β-cell autoimmunity and prevented diabetes onset. Numbers of islet-resident conventional CD4+and CD8+T cells, and DCs were reduced within 4 weeks of AAV8mIP-IL35 treatment. The diminished islet T-cell pool correlated with suppressed proliferation, and a decreased frequency of IFN-γ-expressing Teff. Ectopic IL-35 also reduced islet Foxp3+Treg numbers and proliferation, and protection was independent of induction/expansion of adaptive islet immunoregulatory T cells. These findings demonstrate that IL-35-mediated suppression is sufficiently robust to block established β-cell autoimmunity, and support the use of IL-35 to treat T1D and other T-cell-mediated autoimmune diseases.
authors.affiliation: Department of Microbiology & Immunology, Chapel Hill, NC, USA.
authors.forename: Fatima
authors.initials: F
authors.lastname: Manzoor
authors.affiliation: Department of Microbiology & Immunology, Chapel Hill, NC, USA.
authors.forename: Mark C
authors.initials: MC
authors.lastname: Johnson
authors.affiliation: Gene Therapy Center, Chapel Hill, NC, USA.|Department of Pharmacology, Chapel Hill, NC, USA.
authors.forename: Chengwen
authors.initials: C
authors.lastname: Li
authors.affiliation: Gene Therapy Center, Chapel Hill, NC, USA.|Department of Pharmacology, Chapel Hill, NC, USA.
authors.forename: R Jude
authors.initials: RJ
authors.lastname: Samulski
authors.affiliation: Department of Microbiology & Immunology, Chapel Hill, NC, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Microbiology & Immunology, Chapel Hill, NC, USA.|Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
authors.forename: Roland
authors.initials: R
authors.lastname: Tisch
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D002460:Cell Line; D000229:Dependovirus / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology* / Q000628:therapy; D004195:Disease Models, Animal; D000066630:Ectopic Gene Expression; D005260:Female; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D006801:Humans; D050417:Insulin-Secreting Cells / Q000276:immunology* / Q000378:metabolism*; D007378:Interleukins / Q000235:genetics* / Q000378:metabolism; D007515:Islets of Langerhans / Q000276:immunology / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D009928:Organ Specificity; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D014161:Transduction, Genetic
chemical_list: D007378:Interleukins; D012333:RNA, Messenger; C569375:interleukin-35, mouse
keywords: Cytokine immunotherapy; IL-35; NOD mice; Type 1 diabetes; β cell