Granulocyte-colony stimulating factor treatment of lupus autoimmune disease in MRL-lpr/lpr mice.
G-CSF not only functions as an endogenous hemopoietic growth factor for neutrophils, but also displays pro-Th2 and antiinflammatory properties that could be of therapeutic benefit in autoimmune settings. We evaluated the effect of treatment with G-CSF in a murine model of spontaneous systemic lupus erythematosus, a disease in which G-CSF is already administered to patients to alleviate neutropenia, a common complication. Chronic treatment of lupus-prone MRL-lpr/lpr mice with low doses (10 microg/kg) of recombinant human G-CSF, despite the induction of a shift toward the Th2 phenotype of the autoimmune response, increased glomerular deposition of Igs and accelerated lupus disease. Conversely, high-dose (200 microg/kg) treatment with G-CSF induced substantial protection, prolonging survival by >2 mo. In the animals treated with these high doses of G-CSF, neither the Th1/Th2 profile nor the serum levels of TNF-alpha and IL-10 were modified. Despite the presence of immune complexes in their kidney glomeruli, no inflammation ensued, and serum IL-12 and soluble TNF receptors remained at pre-disease levels. This uncoupling of immune complex deposition and kidney damage resulted from a local down-modulation of FcgammaRIII (CD16) expression within the glomeruli by G-CSF. Our results demonstrate a beneficial effect of high doses of G-CSF in the prevention of lupus nephritis that may hold promise for future clinical applications, provided caution is taken in dose adjustment.
Zavala
F
F
Institut National de la Santé et de la Recherche Médicale Unité 25, Hôpital Necker, Paris, France. zavala@necker.fr
Masson
A
A
Hadaya
K
K
Ezine
S
S
Schneider
E
E
Babin
O
O
Bach
J F
JF
D000419:Albuminuria / Q000235:genetics / Q000401:mortality / Q000517:prevention & control; D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D004306:Dose-Response Relationship, Immunologic; D004334:Drug Administration Schedule; D005260:Female; D020022:Genetic Predisposition to Disease; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage* / Q000494:pharmacology; D007111:Immunity, Cellular / Q000187:drug effects; D007132:Immunoglobulin Isotypes / Q000096:biosynthesis; D007279:Injections, Subcutaneous; D007678:Kidney Glomerulus / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008181:Lupus Nephritis / Q000209:etiology / Q000235:genetics / Q000276:immunology* / Q000401:mortality; D051379:Mice; D019463:Mice, Inbred MRL lpr; D017452:Receptors, IgG / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D013154:Spleen / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology
D001323:Autoantibodies; D016207:Cytokines; D007132:Immunoglobulin Isotypes; D017452:Receptors, IgG; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor