Pharmacodynamic effects of everolimus on anti-CD3 antibody-stimulated T-lymphocyte proliferation and interleukin-10 synthesis in stable kidney-transplant patients.
Everolimus (rapamycin derivative, RAD) is a new immunosuppressive drug that prevents allograft rejection. Herein, the pharmacodynamics of everolimus in human renal-allograft recipients is evaluated. Single doses of everolimus (0.75-10mg), combined with a maintenance immunosuppressive therapy based on CyA, decreased lymphocyte proliferation. In addition, the effect of multiple doses of everolimus (0.75-10mg) given daily for 21 days, to stable renal-allograft patients (n=11), was investigated. Everolimus treatment resulted in immediate inhibition (25-55%) of lymphocyte proliferation in renal-allograft recipients; values returning to baseline by 14 days after cessation of everolimus treatment. Placebo-treated patients showed no decrease in lymphocyte proliferation. Interestingly, everolimus reduced IL-10 synthesis by 20-60% in renal-allograft recipients. Phagocytosis rates were not changed by everolimus. In vitro, everolimus inhibited lymphocyte proliferation and IL-10 synthesis dose dependently in anti-CD3 mAb and LPS stimulated peripheral blood mononuclear cell cultures derived from human volunteers.
Böhler
Torsten
T
INSERM U858, I2MR, Eq. 10, Institut Louis Bugnard, Bâtiment L3, CHU Rangueil, 1 Avenue J Poulhès, 31403 Toulouse Cedex 4, France. boehlert@toulouse.inserm.fr
Waiser
Johannes
J
Lichter
Steffi
S
Schumann
Brit
B
Neumayer
Hans-H
HH
Kamar
Nassim
N
Budde
Klemens
K
D000328:Adult; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D017252:CD3 Complex / Q000276:immunology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004311:Double-Blind Method; D016903:Drug Monitoring; D000068338:Everolimus; D005260:Female; D006084:Graft Rejection / Q000276:immunology; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D016753:Interleukin-10 / Q000096:biosynthesis*; D016030:Kidney Transplantation / Q000276:immunology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D010587:Phagocytosis; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology*
D000911:Antibodies, Monoclonal; D017252:CD3 Complex; C508609:IL10 protein, human; D007166:Immunosuppressive Agents; D008070:Lipopolysaccharides; D016753:Interleukin-10; D000068338:Everolimus; D020123:Sirolimus