Inhibitory effect of plasma FKBP12 on immunosuppressive activity of FK506

Abstract

To evaluate the roles of extracellular FKBP12, we examined the effect of extracellular FKBP12 on the immunosuppressive activity of FK506 in vitro and clinically. The ability of FK506 to suppress phytohemagglutinin-induced proliferative response of human peripheral blood mononuclear cells was inhibited in the presence of recombinant FKBP12 dose-dependently. We measured plasma levels of FKBP12 using a newly developed enzyme-linked immunosorbent assay system in 34 patients receiving FK506 after liver transplantation. In 7 patients with acute cellular rejection, plasma FKBP12 increased significantly at the onset of rejection compared with 1 week before onset (P < 0.05) and further increased to or remained at more than 250 ng/ml 1 week after onset. In 22 of 27 patients without acute cellular rejection, plasma FKBP12 was less than 70 ng/ml during the 4 weeks after transplantation. In the other 5 of 27 patients without acute cellular rejection, plasma FKBP12 exceeded 250 ng/ml. Rapid increase of plasma FKBP12 was observed in only one of these 5 patients, at the onset of high fever due to a liver abscess. There was no significant difference in whole blood trough levels of FK506 between the patients with or without acute cellular rejection. These results suggest that the rapid increase in plasma levels of FKBP12 may contribute to the occurrence and progress of acute cellular rejection probably by inhibiting the immunosuppressive activity of FK506.