Adoptive Transfer of Immunomodulatory M2 Macrophages Prevents Type 1 Diabetes in NOD Mice

  1. Robert A. Harris1
  1. 1Applied Immunology, Center for Molecular Medicine, Karolinska University Hospital at Solna, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
  2. 2Neuroimmunology, Center for Molecular Medicine, Karolinska University Hospital at Solna, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
  3. 3Department of Medical Biosciences, Umeå University, Umeå, Sweden
  1. Corresponding author: Robert A. Harris, robert.harris{at}ki.se.
  1. A.G., S.M., and X.-M.Z. contributed equally to this study.

Abstract

Macrophages are multifunctional immune cells that may either drive or modulate disease pathogenesis depending on their activation phenotype. Autoimmune type 1 diabetes (T1D) is a chronic proinflammatory condition characterized by unresolved destruction of pancreatic islets. Adoptive cell transfer of macrophages with immunosuppressive properties represents a novel immunotherapy for treatment of such chronic autoimmune diseases. We used a panel of cytokines and other stimuli to discern the most effective regimen for in vitro induction of immunosuppressive macrophages (M2r) and determined interleukin-4 (IL-4)/IL-10/transforming growth factor-β (TGF-β) to be optimal. M2r cells expressed programmed cell death 1 ligand-2 (PD-L2), fragment crystallizable region γ receptor IIb (FCγRIIb), IL-10, and TGF-β, had a potent deactivating effect on proinflammatory lipopolysaccharide/interferon-γ–stimulated macrophages, and significantly suppressed T-cell proliferation. Clinical therapeutic efficacy was assessed after adoptive transfer in NOD T1D, and after a single transfer of M2r macrophages, >80% of treated NOD mice were protected against T1D for at least 3 months, even when transfer was conducted just prior to clinical onset. Fluorescent imaging analyses revealed that adoptively transferred M2r macrophages specifically homed to the inflamed pancreas, promoting β-cell survival. We suggest that M2r macrophage therapy represents a novel intervention that stops ongoing autoimmune T1D and may have relevance in a clinical setting.

  • Received November 23, 2011.
  • Accepted May 3, 2012.

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