title: Prevention of autoimmune diabetes by ectopic pancreatic β-cell expression of interleukin-35.
abstract: Interleukin (IL)-35 is a newly identified inhibitory cytokine used by T regulatory cells to control T cell-driven immune responses. However, the therapeutic potential of native, biologically active IL-35 has not been fully examined. Expression of the heterodimeric IL-35 cytokine was targeted to β-cells via the rat insulin promoter (RIP) II. Autoimmune diabetes, insulitis, and the infiltrating cellular populations were analyzed. Ectopic expression of IL-35 by pancreatic β-cells led to substantial, long-term protection against autoimmune diabetes, despite limited intraislet IL-35 secretion. Nonobese diabetic RIP-IL35 transgenic mice exhibited decreased islet infiltration with substantial reductions in the number of CD4(+) and CD8(+) T cells, and frequency of glucose-6-phosphatase catalytic subunit-related protein-specific CD8(+) T cells. Although there were limited alterations in cytokine expression, the reduced T-cell numbers observed coincided with diminished T-cell proliferation and G1 arrest, hallmarks of IL-35 biological activity. These data present a proof of principle that IL-35 could be used as a potent inhibitor of autoimmune diabetes and implicate its potential therapeutic utility in the treatment of type 1 diabetes.
authors.affiliation: Department of Immunology, St Jude Children’s Research Hospital, Memphis, Tennessee, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Bettini
authors.forename: Ashley H
authors.initials: AH
authors.lastname: Castellaw
authors.forename: Greig P
authors.initials: GP
authors.lastname: Lennon
authors.forename: Amanda R
authors.initials: AR
authors.lastname: Burton
authors.forename: Dario A A
authors.initials: DA
authors.lastname: Vignali
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D049109:Cell Proliferation; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D005260:Female; D015870:Gene Expression; D050417:Insulin-Secreting Cells / Q000276:immunology / Q000378:metabolism*; D007378:Interleukins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*
chemical_list: D007378:Interleukins; C569375:interleukin-35, mouse