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Sustained in vivo signaling by long-lived IL-2 induces prolonged increases of regulatory T cells.

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  • Additional Information
    • Publication Information:
      Elsevier BV
      //doi.org/10.1016/j.jaut.2014.10.002
      J Autoimmun
    • Publication Date:
      2015
    • Collection:
      Apollo - University of Cambridge Repository
    • Abstract:
      Regulatory T cells (Tregs) expressing FOXP3 are essential for the maintenance of self-tolerance and are deficient in many common autoimmune diseases. Immune tolerance is maintained in part by IL-2 and deficiencies in the IL-2 pathway cause reduced Treg function and an increased risk of autoimmunity. Recent studies expanding Tregs in vivo with low-dose IL-2 achieved major clinical successes highlighting the potential to optimize this pleiotropic cytokine for inflammatory and autoimmune disease indications. Here we compare the clinically approved IL-2 molecule, Proleukin, with two engineered IL-2 molecules with long half-lives owing to their fusion in monovalent and bivalent stoichiometry to a non-FcRγ binding human IgG1. Using nonhuman primates, we demonstrate that single ultra-low doses of IL-2 fusion proteins induce a prolonged state of in vivo activation that increases Tregs for an extended period of time similar to multiple-dose Proleukin. One of the common pleiotropic effects of high dose IL-2 treatment, eosinophilia, is eliminated at doses of the IL-2 fusion proteins that greatly expand Tregs. The long half-lives of the IL-2 fusion proteins facilitated a detailed characterization of an IL-2 dose response driving Treg expansion that correlates with increasingly sustained, suprathreshold pSTAT5a induction and subsequent sustained increases in the expression of CD25, FOXP3 and Ki-67 with retention of Treg-specific epigenetic signatures at FOXP3 and CTLA4. ; This work was supported by Wellcome Trust Grant 091157, JDRF International Grant 9-2011-253, the National Institute for Health Research Cambridge Biomedical Research Centre, and the Medical Research Council Cusrow Wadia Fund. The Cambridge Institute for Medical Research (CIMR) is in receipt of a Wellcome Trust Strategic Award (100140). U.M.N. was the recipient of a Hoffmann-La Roche postdoctoral fellowship. ; This is thefinal version. It was first published by Elsevier at http://www.sciencedirect.com/science/article/pii/S0896841114001462
    • File Description:
      application/pdf
    • Relation:
      https://www.repository.cam.ac.uk/handle/1810/246183
    • Online Access:
      https://www.repository.cam.ac.uk/handle/1810/246183
    • Rights:
      Attribution 2.0 UK: England & Wales ; http://creativecommons.org/licenses/by/2.0/uk/
    • Accession Number:
      edsbas.909C2255