Mycophenolic acid-treated human dendritic cells have a mature migratory phenotype and inhibit allogeneic responses via direct and indirect pathways.
Immature dendritic cells (DCs) can induce T-cell hyporesponsiveness, thus interfering with the process of DC maturation in a pro-inflammatory context, may therefore provide a novel approach to inducing allograft tolerance. We have studied the effects of mycophenolic acid (MPA), an immunosuppressive agent currently used in transplantation, using an in vitro model of a mixed human DC/alloreactive CD4(+) T lymphocyte culture. DCs differentiated from monocytes were exposed to MPA during maturation. MPA treatment affected the maturation of DCs, and this was reflected both in the impairment of the up-regulation of co-stimulatory molecule expression and the maintained endocytic capacity. However, MPA-DCs exhibited a distinctive microscopic morphology and secreted IL-10 and so could no longer be regarded as immature DC. Moreover, MPA-DCs had a mature phenotype for chemokine receptor expression, exhibiting down-regulation of CCR5 and up-regulation of CCR7. Interestingly, the abilities of the MPA-DCs to induce CD4(+) T-cell proliferation in response to alloantigens was impaired not only via direct but also via indirect pathways. The maintenance of endocytosis and the inhibition of syngeneic T-cell activation suggest that these cells could have a potential role to avoid chronic rejection. All these characteristics suggest that MPA-DCs may be used in cell therapy to induce allograft tolerance.
Lagaraine
Christine
C
JE 2448, Cellules Dendritiques et Greffes, IFR 135, Imagerie et exploration fonctionnelles, Université François Rabelais, 2 bis Bd Tonnelle, 37032 Tours, France.
Hoarau
Cyrille
C
Chabot
Valérie
V
Velge-Roussel
Florence
F
Lebranchu
Yvon
Y
D017209:Apoptosis / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D003713:Dendritic Cells / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors*; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D009173:Mycophenolic Acid / Q000494:pharmacology*
D007168:IMP Dehydrogenase; D009173:Mycophenolic Acid