Treatment with granulocyte colony-stimulating factor prevents diabetes in NOD mice by recruiting plasmacytoid dendritic cells and functional CD4(+)CD25(+) regulatory T-cells.
Accumulating evidence that granulocyte colony-stimulating factor (G-CSF), the key hematopoietic growth factor of the myeloid lineage, not only represents a major component of the endogenous response to infections, but also affects adaptive immune responses, prompted us to investigate the therapeutic potential of G-CSF in autoimmune type 1 diabetes. Treatment with G-CSF protected NOD mice from developing spontaneous diabetes. G-CSF triggered marked recruitment of dendritic cells (DCs), particularly immature CD11c(lo)B220(+) plasmacytoid DCs, with reduced costimulatory signal expression and higher interferon-alpha but lower interleukin-12p70 release capacity than DCs in excipient-treated mice. G-CSF recipients further displayed accumulation of functional CD4(+)CD25(+) regulatory T-cells that produce transforming growth factor-beta1 (TGF-beta1) and actively suppressed diabetes transfer by diabetogenic effector cells in secondary NOD-SCID recipients. G-CSF's ability to promote key tolerogenic interactions between DCs and regulatory T-cells was demonstrated by enhanced recruitment of TGF-beta1-expressing CD4(+)CD25(+) cells after adoptive transfer of DCs isolated from G-CSF- relative to vehicle-treated mice into naive NOD recipients. The present results suggest that G-CSF, a promoter of tolerogenic DCs, may be evaluated for the treatment of human type 1 diabetes, possibly in association with direct inhibitors of T-cell activation. They also provide a rationale for a protective role of the endogenous G-CSF produced during infections in early diabetes.
Kared
Hassen
H
DSc, INSERM U580, Necker Institute, 161 rue de Sèvres, 75743 Paris Cedex 15, France.
Masson
Annie
A
Adle-Biassette
Homa
H
Bach
Jean-François
JF
Chatenoud
Lucienne
L
Zavala
Flora
F
D000375:Aging; D000818:Animals; D015704:CD4 Antigens / Q000187:drug effects / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D016207:Cytokines / Q000276:immunology; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000517:prevention & control; D005260:Female; D005434:Flow Cytometry; D016179:Granulocyte Colony-Stimulating Factor / Q000627:therapeutic use*; D051379:Mice; D016688:Mice, Inbred NOD; D015375:Receptors, Interleukin-2 / Q000187:drug effects / Q000276:immunology*; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta / Q000276:immunology; D053773:Transforming Growth Factor beta1
D015704:CD4 Antigens; D016207:Cytokines; D015375:Receptors, Interleukin-2; D011994:Recombinant Proteins; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D016179:Granulocyte Colony-Stimulating Factor