G-CSF treatment prevents cyclophosphamide acceleration of autoimmune diabetes in the NOD mouse.
Cyclophosphamide (CY) accelerates autoimmune diabetes in the NOD mouse at different levels, including critical targeting of a regulatory T cell subset, exacerbation of pro-Th1 IFN-gamma production and promotion of inflammation in pancreatic islets. Here we evaluated the ability of G-CSF to antagonize the acceleration of the disease induced by CY. Human recombinant G-CSF, administered daily at 200 microg/kg by s.c. injection, protected NOD mice from CY-accelerated onset of glycosuria and insulitis. G-CSF accelerated the recovery of the T cell compartment after the depletion of the lymphoid compartment triggered by CY injection. It selectively prevented the loss of the immunoregulatory T cells expressing the CD4(+)CD25+ phenotype that also stained CD62L+ in peripancreatic lymph nodes and promoted their expansion in the spleen. In addition to this, it abrogated the robust cytokine--particularly IFN-gamma- and chemokine burst triggered in immune cells by CY. G-CSF promoted only slight changes in the inflammatory effects of CY at the target tissue site, assessed by chemokine induction within the pancreas. Thus the immunoregulatory properties of G-CSF were critical in the early control of the accelerating effects of CY on autoimmune diabetes in the NOD mouse.
Hadaya
Karine
K
Institut National de la Santé et de la Recherche Médicale INSERM U580, Institut de Recherche Necker Enfants Malades, Hôpital Necker, 161 rue de Sèvres, 75743 Paris Cedex 15, France.
Kared
Hassen
H
Masson
Annie
A
Chatenoud
Lucienne
L
Zavala
Flora
F
D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018925:Chemokines / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D003520:Cyclophosphamide / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000139:chemically induced* / Q000150:complications / Q000276:immunology / Q000473:pathology*; D018450:Disease Progression; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D018655:Lymphocyte Count; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D022423:Myeloid Cells / Q000166:cytology / Q000187:drug effects; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics
D015703:Antigens, CD; D018925:Chemokines; D016207:Cytokines; D012333:RNA, Messenger; D016179:Granulocyte Colony-Stimulating Factor; D003520:Cyclophosphamide