title: Inhibition of Autoimmune Diabetes in NOD Mice by miRNA Therapy.
abstract: Autoimmune destruction of the pancreatic islets in Type 1 diabetes is mediated by both increased proinflammatory (Teff) and decreased regulatory (Treg) T lymphocytes resulting in a significant decrease in the Treg:Teff ratio. The non-obese diabetic (NOD) mouse is an excellent in vivo model for testing potential therapeutics for attenuating the decrease in the Treg:Teff ratio and inhibiting disease pathogenesis. Here we show for the first time that a bioreactor manufactured therapeutic consisting of a complex of miRNA species (denoted as TA1) can effectively reset the NOD immune system from a proinflammatory to a tolerogenic state thus preventing or delaying autoimmune diabetes. Treatment of NOD mice with TA1 resulted in a systemic broad-spectrum upregulation of tolerogenic T cell subsets with a parallel downregulation of Teff subsets yielding a dramatic increase in the Treg:Teff ratio. Moreover, the murine-derived TA1 was highly effective in the inhibition of allorecognition of HLA-disparate human PBMC. TA1 demonstrated dose-responsiveness and exhibited equivalent or better inhibition of allorecognition driven proliferation than etanercept (a soluble TNF receptor). These findings demonstrate that miRNA-based therapeutics can effectively attenuate or arrest autoimmune disease processes and may be of significant utility in a broad range of autoimmune diseases including Type 1 diabetes.
authors.affiliation: Centre for Innovation, Canadian Blood Services, Ottawa, Ontario, Canada.|Centre for Blood Research, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Duncheng
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Iryna
authors.initials: I
authors.lastname: Shanina
authors.affiliation: Centre for Innovation, Canadian Blood Services, Ottawa, Ontario, Canada.|Centre for Blood Research, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Wendy M
authors.initials: WM
authors.lastname: Toyofuku
authors.affiliation: Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Marc S
authors.initials: MS
authors.lastname: Horwitz
authors.affiliation: Centre for Innovation, Canadian Blood Services, Ottawa, Ontario, Canada.|Centre for Blood Research, University of British Columbia, Vancouver, British Columbia, Canada.|Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Scott
mesh_terms: D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000628:therapy*; D051379:Mice; D016688:Mice, Inbred NOD; D000067492:RNAi Therapeutics; D050378:T-Lymphocytes, Regulatory / Q000276:immunology