title: Adoptive transfer of immunomodulatory M2 macrophages prevents type 1 diabetes in NOD mice.
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 (IL)-4/IL-10/transforming growth factor-β (TGF-β) to be optimal. M2r cells expressed programmed cell death 1 ligand-2, fragment crystallizable region γ receptor IIb, 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 mice, 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.
authors: Applied Immunology, Center for Molecular Medicine, Karolinska University Hospital at Solna, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors: Roham
authors: R
authors: Parsa
authors: Pernilla
authors: P
authors: Andresen
authors: Alan
authors: A
authors: Gillett
authors: Sohel
authors: S
authors: Mia
authors: Xing-Mei
authors: XM
authors: Zhang
authors: Sofia
authors: S
authors: Mayans
authors: Dan
authors: D
authors: Holmberg
authors: Robert A
authors: RA
authors: Harris
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D058948:Cell Tracking; D002478:Cells, Cultured; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D005260:Female; D005786:Gene Expression Regulation; D016219:Immunotherapy, Adoptive; D050417:Insulin-Secreting Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D059425:Interferon-gamma Release Tests; D016753:Interleukin-10 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation*; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D010179:Pancreas / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D011236:Prediabetic State / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D012333:RNA, Messenger / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: C556062:IL10 protein, mouse; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D015847:Interleukin-4