Immune regulatory neural stem/precursor cells protect from central nervous system autoimmunity by restraining dendritic cell function.
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.
Pluchino
Stefano
S
Neuroimmunology Unit, San Raffaele Scientific Institute and Università Vita-Salute, Milan, Italy. pluchino.stefano@hsr.it
Zanotti
Lucia
L
Brambilla
Elena
E
Rovere-Querini
Patrizia
P
Capobianco
Annalisa
A
Alfaro-Cervello
Clara
C
Salani
Giuliana
G
Cossetti
Chiara
C
Borsellino
Giovanna
G
Battistini
Luca
L
Ponzoni
Maurilio
M
Doglioni
Claudio
C
Garcia-Verdugo
Jose Manuel
JM
Comi
Giancarlo
G
Manfredi
Angelo A
AA
Martino
Gianvito
G
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*
D019485:Bone Morphogenetic Proteins