Assessment of mycophenolic acid-induced immunosuppression: a new approach.
BACKGROUND
Mycophenolic acid (MPA), a metabolite of mycophenolate mofetil (MMF), is an immunosuppressive agent that inhibits inosine monophosphate dehydrogenase (IMPDH), a key enzyme in the ex novo synthesis of GTP. We measured IMPDH activity in peripheral blood mononuclear cells (PBMCs) from MMF-treated patients to evaluate the efficacy of MMF in individual patients.


METHODS
IMPDH activity was measured by (3)H released from [2,8-(3)H]IMP that had been formed in the cells from added [2,8-(3)H]hypoxanthine in PBMCs of 35 renal transplant recipients treated with cyclosporin A and corticoids plus MMF: 2 g (n = 10), 1.5 g (n = 7), 1 g (n = 10), or 0 g (n = 8) per day. An alternative method, based on the capacity of the patients' sera to inhibit spontaneous proliferation of the CEM cell line, was also analyzed.


RESULTS
The IMPDH activity of PBMCs in transplanted patients was highly variable. For the method based on CEM cell line proliferation: (a) cell proliferation was inhibited only in MMF-treated patients; (b) there was a clear postdose increase in inhibition; (c) inhibition was not affected by other immunosuppressants in vitro or in vivo; (d) inhibition from predose to predose sample was correlated; and (e) when the MMF dosage was <20 mg. kg(-1). day(-1), two groups of patients were identified, one that maintained a high inhibitory capacity in all dose intervals, and one with periods of low inhibitory capacity.


CONCLUSIONS
Measurement of the inhibition of CEM cell line proliferation by sera from MMF-treated patients may be useful for evaluating the relative efficacy of MMF treatment in individual patients, especially those receiving low doses of MMF.
Millan
O
O
Servei Immunologia Toxicologia i Unitat de Transplantament Renal, IDIBAPS, Hospital Clinic, C/Villarroel 170, 08036 Barcelona, Spain.
Oppenheimer
F
F
Brunet
M
M
Vilardell
J
J
Rojo
I
I
Vives
J
J
Martorell
J
J
D000328:Adult; D002455:Cell Division / Q000187:drug effects; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007168:IMP Dehydrogenase / Q000097:blood; D007166:Immunosuppressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007963:Leukocytes, Mononuclear / Q000201:enzymology; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000494:pharmacology* / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
D007166:Immunosuppressive Agents; D007168:IMP Dehydrogenase; D009173:Mycophenolic Acid