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.

Highlights

  • Autoimmune destruction of pancreatic islets in Type 1 Diabetes (T1D) occurs via T-lymphocyte (T cell) dependent pathways.[1,2,3] Elucidation of the role of T cells in T1D has been most effectively examined in the non-obese diabetic (NOD) mouse model

  • In the NOD mouse, evidence suggests that a deficit in regulatory T cell (Treg) control over diabetogenic T effector (Teff) cells leads to the development of insulitis and disease.[2,3,4,5,6,7,8,9,10,11,12]

  • We previously demonstrated that allorecognition of HLA/MHC-disparate donor leukocytes could be abrogated by the covalent grafting of methoxypolyethylene glycol to the membrane of cells.[31,32,33,34,35,36,37,38]

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Summary

Introduction

Autoimmune destruction of pancreatic islets in Type 1 Diabetes (T1D) occurs via T-lymphocyte (T cell) dependent pathways.[1,2,3] Elucidation of the role of T cells in T1D has been most effectively examined in the non-obese diabetic (NOD) mouse model. In the NOD mouse, evidence suggests that a deficit in regulatory T cell (Treg) control over diabetogenic T effector (Teff) cells leads to the development of insulitis and disease.[2,3,4,5,6,7,8,9,10,11,12] changes in the Treg:Teff ratio (i.e., balance) occurring at 3–4 weeks of age initiates disease progression.[2] Consistent with the murine findings, human studies have demonstrated that T1D Tregs exhibit.

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