G-CSF therapy of ongoing experimental allergic encephalomyelitis via chemokine- and cytokine-based immune deviation.
Converging evidence that G-CSF, the hemopoietic growth factor of the myeloid lineage, also exerts anti-inflammatory and pro-Th2 effects, prompted us to evaluate its direct therapeutic potential in autoimmune diseases. Here we report a novel activity of G-CSF in experimental allergic encephalomyelitis, a murine model for multiple sclerosis, driven by Th1-oriented autoaggressive cells. A short 7-day treatment with G-CSF, initiated at the onset of clinical signs, provided durable protection from experimental autoimmune encephalomyelitis. G-CSF-treated mice displayed limited demyelination, reduced recruitment of T cells to the CNS, and very discrete autoimmune inflammation, as well as barely detectable CNS mRNA levels of cytokines and chemokines. In the periphery, G-CSF treatment triggered an imbalance in the production by macrophages as well as autoreactive splenocytes of macrophage inflammatory protein-1alpha and monocyte chemoattractant protein-1, the prototypical pro-Th1 and pro-Th2 CC chemokines, respectively. This chemokine imbalance was associated with an immune deviation of the autoreactive response, with reduced IFN-gamma and increased IL-4 and TGF-beta1 levels. Moreover, G-CSF limited the production of TNF-alpha, a cytokine also associated with early CNS infiltration and neurological deficit. These findings support the potential application of G-CSF in the treatment of human autoimmune diseases such as multiple sclerosis, taking advantage of the wide clinical favorable experience with this molecule.
Zavala
Flora
F
Institut National de la Santé et de la Recherche Médical, Unité 25 and Unité 345, Necker Hospital, Paris, France. Sanofi-Synthelabo, Bagneux, France. zavala@necker.fr
Abad
Sébastien
S
Ezine
Sophie
S
Taupin
Véronique
V
Masson
Annie
A
Bach
Jean-François
JF
D000818:Animals; D002478:Cells, Cultured; D002531:Cerebellum / Q000473:pathology; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000235:genetics; D054407:Chemokine CCL4; D018925:Chemokines / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology / Q000627:therapeutic use*; D006098:Granulocytes / Q000187:drug effects / Q000276:immunology; D016298:Hematopoietic Cell Growth Factors / Q000096:biosynthesis / Q000235:genetics; D007700:Kinetics; D019402:Macrophage Inflammatory Proteins / Q000096:biosynthesis / Q000235:genetics; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D051379:Mice; D009186:Myelin Sheath / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis; D013116:Spinal Cord / Q000276:immunology / Q000473:pathology; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics
D018932:Chemokine CCL2; D054407:Chemokine CCL4; D018925:Chemokines; D016207:Cytokines; D016298:Hematopoietic Cell Growth Factors; D019402:Macrophage Inflammatory Proteins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D016179:Granulocyte Colony-Stimulating Factor