title: Immune regulatory neural stem/precursor cells protect from central nervous system autoimmunity by restraining dendritic cell function.
abstract: BACKGROUND
  The systemic injection of neural stem/precursor cells (NPCs) provides remarkable amelioration of the clinico-pathological features of experimental autoimmune encephalomyelitis (EAE). This is dependent on the capacity of transplanted NPCs to engage concurrent mechanisms of action within specific microenvironments in vivo. Among a wide range of therapeutic actions alternative to cell replacement, neuroprotective and immune modulatory capacities of transplanted NPCs have been described. However, lacking is a detailed understanding of the mechanisms by which NPCs exert their therapeutic plasticity. This study was designed to identify the first candidate that exemplifies and sustains the immune modulatory capacity of transplanted NPCs.
  
  
  RESULTS
  To achieve the exclusive targeting of the peripheral immune system, SJL mice with PLP-induced EAE were injected subcutaneously with NPCs and the treatment commenced prior to disease onset. NPC-injected EAE mice showed significant clinical improvement, as compared to controls. Exogenous NPCs lacking the expression of major neural antigens were reliably (and for long-term) found at the level of draining lymph nodes, while establishing sophisticated anatomical interactions with lymph node cells. Importantly, injected NPCs were never found in organs other than lymph nodes, including the brain and the spinal cord. Draining lymph nodes from transplanted mice showed focal up-regulation of major developmental stem cell regulators, such as BMP-4, Noggin and Sonic hedgehog. In lymph nodes, injected NPCs hampered the activation of myeloid dendritic cells (DCs) and steadily restrained the expansion of antigen-specific encephalitogenic T cells. Both ex vivo and in vitro experiments identified a novel highly NPC-specific-BMP-4-dependent-mechanism hindering the DC maturation.
  
  
  CONCLUSIONS
  The study described herein, identifies the first member of the TGF beta/BMP family of stem cell regulators as a novel tolerogenic factor released by NPCs. Full exploitation of this pathway as an efficient tool for vaccination therapy in autoimmune inflammatory conditions is underway.
authors: Neuroimmunology Unit, San Raffaele Scientific Institute and Università Vita-Salute, Milan, Italy. pluchino.stefano@hsr.it
authors: Stefano
authors: S
authors: Pluchino
authors: Lucia
authors: L
authors: Zanotti
authors: Elena
authors: E
authors: Brambilla
authors: Patrizia
authors: P
authors: Rovere-Querini
authors: Annalisa
authors: A
authors: Capobianco
authors: Clara
authors: C
authors: Alfaro-Cervello
authors: Giuliana
authors: G
authors: Salani
authors: Chiara
authors: C
authors: Cossetti
authors: Giovanna
authors: G
authors: Borsellino
authors: Luca
authors: L
authors: Battistini
authors: Maurilio
authors: M
authors: Ponzoni
authors: Claudio
authors: C
authors: Doglioni
authors: Jose Manuel
authors: JM
authors: Garcia-Verdugo
authors: Giancarlo
authors: G
authors: Comi
authors: Angelo A
authors: AA
authors: Manfredi
authors: Gianvito
authors: G
authors: Martino
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000276:immunology*; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D017690:Cell Transplantation; D002490:Central Nervous System / Q000276:immunology*; D003713:Dendritic Cells / Q000166:cytology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology; D005260:Female; D007107:Immune System; D007249:Inflammation; D008198:Lymph Nodes / Q000473:pathology; D051379:Mice; D008854:Microscopy, Electron / Q000379:methods; D009474:Neurons / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology*
chemical_list: D019485:Bone Morphogenetic Proteins