Expression of IMPDH1 and IMPDH2 after transplantation and initiation of immunosuppression.
BACKGROUND
Mycophenolic acid (MPA) mediates immunosuppressive effects by inhibiting inosine monophosphate dehydrogenase (IMPDH). Induction of IMPDH activity has been observed in whole blood and erythrocyte samples during immunosuppressive therapy. Information concerning the mechanisms for increased IMPDH activity is limited and the potential implications of induction have been debated.


METHODS
Whole blood, CD4+ cell, and reticulocyte samples were collected from 30 renal transplant patients pre- and posttransplantation. The expressions of two IMPDH isoforms, type 1 and 2, were analyzed by real-time reverse-transcription polymerase chain reaction and quantified using a housekeeping gene index. The IMPDH activity was determined by ultraviolet high-performance liquid chromatography.


RESULTS
Transplantation and the initiation of immunosuppressive therapy was associated with increased IMPDH1 (50-88%, P<0.0005) and decreased IMPDH2 (42-56%, P<0.0005) expression. In CD4+ cells, however, IMPDH2 increased (15%, P=0.009). These changes are probably related to glucocorticoid effects. Two weeks posttransplant, MPA-treated patients displayed elevated IMPDH 1 and 2 in reticulocytes, suggesting enzyme induction in these cells during prolonged MPA therapy. Patients with acute rejection during follow-up demonstrated higher IMPDH2 expression in CD4+ cells pretransplant than nonrejecting patients (median expression 1.26 vs. 0.87 respectively, P=0.017).


CONCLUSIONS
Knowledge of changes in IMPDH 1 and 2 expression after transplantation and initiation of immunosuppression is important considering the action of MPA on IMPDH and the potential for pharmacodynamic monitoring of MPA by measuring IMPDH activity. The expression of IMPDH2 in CD4+ cells pretransplant may be an indicator of immune activation.
Bremer
Sara
S
Department of Medical Biochemistry, Rikshospitalet Medical Centre, Institute of Clinical Biochemistry, University of Oslo, Norway.
Mandla
Randeep
R
Vethe
Nils T
NT
Rasmussen
Ingrid
I
Rootwelt
Helge
H
Line
Pål-D
PD
Midtvedt
Karsten
K
Bergan
Stein
S
D000328:Adult; D000368:Aged; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006084:Graft Rejection / Q000276:immunology; D006801:Humans; D007168:IMP Dehydrogenase / Q000097:blood*; D007165:Immunosuppression Therapy; D007527:Isoenzymes / Q000097:blood; D016030:Kidney Transplantation / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000494:pharmacology; D011446:Prospective Studies
D004791:Enzyme Inhibitors; D007527:Isoenzymes; D007168:IMP Dehydrogenase; C488211:IMPDH1 protein, human; C501687:IMPDH2 protein, human; D009173:Mycophenolic Acid