Adoptive Transfer of Immunomodulatory M2 Macrophages Prevents Type 1 Diabetes in NOD Mice
- Roham Parsa1,
- Pernilla Andresen1,
- Alan Gillett2,
- Sohel Mia1,
- Xing-Mei Zhang1,
- Sofia Mayans3,
- Dan Holmberg3 and
- Robert A. Harris1⇓
- 1Applied Immunology, Center for Molecular Medicine, Karolinska University Hospital at Solna, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
- 2Neuroimmunology, Center for Molecular Medicine, Karolinska University Hospital at Solna, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
- 3Department of Medical Biosciences, Umeå University, Umeå, Sweden
- Corresponding author: Robert A. Harris, .
A.G., S.M., and X.-M.Z. contributed equally to this study.
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.
- © 2012 by the American Diabetes Association.
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