Diabetes acceleration by cyclophosphamide in the non-obese diabetic mouse is associated with differentiation of immunosuppressive monocytes into immunostimulatory cells.
Cyclophosphamide (CTX) was previously shown to induce the recruitment of immunosuppressive myeloid cells in mouse. In the non-obese diabetic (NOD) mouse, which develops spontaneously type I diabetes, CTX is widely known to accelerate the autoimmune process. Our data demonstrated that CTX actually did mobilize an immunosuppressive myeloid CD11b(+) Ly-6G(-) population in the NOD mouse spleen in addition to a well-identified neutrophil CD11b(+) Ly-6G(+) population. CD11b(+) Ly-6G(-) cells, in contrast with CD11b(+) Ly-6G(+) cells, were able to inhibit in vitro mitogen-induced syngeneic T cell proliferation. CD11b(+) Ly-6G(-) cells represented a heterogeneous population mainly made of CD31(hi) cells and Ly-6C(+) monocytes. Only these last ones supported the immunosuppressive in vitro activity and resembled circulating inflammatory monocytes according to flow cytometry, cytology and RT-PCR data. Although CD11b(+) Ly-6G(-) Ly-6C(+) cells exhibited immunosuppressive function in vitro, they were not able to control the autoimmune response following CTX injection. Our data show that these CTX-induced immunosuppressive myeloid cells actually behaved as very plastic cells in vitro. Likewise, in the model of prediabetic NOD/SCID mice, CD11b(+) Ly-6G(-) Ly-6C(+) were able to differentiate into CD11c+ cells after i.v. injection. Herein, we described a new mechanism by which CTX might induce diabetes acceleration in the NOD mouse. In summary, recruited immunosuppressive cells might participate in the immunopotentiating effect of CTX on the autoimmune response by their further differentiation into immunostimulatory cells.
Immuno-Endocrinology Unit, INRA U707, F-44307 Nantes, France.
Marylène
M
Caquard
Stéphanie
S
Ferret-Bernard
Karine
K
Haurogné
Michèle
M
Ouary
Marie
M
Allard
Dominique
D
Jégou
Jean-Marie
JM
Bach
Blandine
B
Lieubeau
D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D003520:Cyclophosphamide / Q000494:pharmacology*; D003920:Diabetes Mellitus / Q000276:immunology* / Q000503:physiopathology; D005434:Flow Cytometry; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009000:Monocytes / Q000166:cytology* / Q000187:drug effects* / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction
D007166:Immunosuppressive Agents; D003520:Cyclophosphamide