title: Ex vivo lymphocyte proliferative function is severely inhibited in renal transplant patients on mycophenolate mofetil treatment.
abstract: Mycophenolate mofetil (MMF) is a recently introduced immunosuppressive drug. Its active form is mycophenolic acid (MPA). MPA specifically inhibits de novo purine synthesis, which is vital for T and B lymphocyte proliferation. We measured lymphocyte subset numbers and mitogen induced proliferation in kidney transplant recipients on different combinations of MMF, cyclosporin A (C), azathioprine (A) and prednisolone (P) (C+A n=70; C+A+P n=15; C+MMF n=45; C+MMF+P n=37) and normals (n=73). Patients on MMF had severely reduced phytohaemagglutinin A (PHA) induced proliferation compared to normals (Nml 2766+/-926 CPM/1000 lymphocytes [mean+/-S.D.]; C+MMF 282+/-406; C+MMF+P 195+/-496); non-MMF patients did not differ from normal. Similar inhibition of Poke Weed Mitogen and Staphylococcal enterotoxin B induced proliferation was observed. Cell cycle studies established that MMF patients had a significantly higher proportion of lymphocytes in the G0/G1 phase following PHA stimulation than the non-MMF patients. All transplant groups had significantly lower B cell numbers than the normal controls but no differences in CD4 and CD8 T cell numbers. All but the C+MMF group had significantly lower CD16+NK cell numbers than normal, while only the non-MMF groups had significantly lower CD56+NK cell numbers. The proliferation assay used was an ex vivo diluted whole blood technique. Removal of residual MPA by washing the plasma out prior to mitogen stimulation led to a significant increase in proliferation in six out of seven cases. In summary we have found that MMF treatment has a strikingly inhibitory effect on patient ex vivo lymphocyte mitogenic function.
authors.affiliation: Department of Medicine, Monash University Monash Medical Centre, 246 Clayton Road, Clayton, VIC 3168, Australia. Paul.Hutchinson@med.monash.edu.au
authors.forename: Paul
authors.initials: P
authors.lastname: Hutchinson
authors.forename: Matthew
authors.initials: M
authors.lastname: Jose
authors.forename: Robert C
authors.initials: RC
authors.lastname: Atkins
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Holdsworth
mesh_terms: D000328:Adult; D001379:Azathioprine / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology; D005260:Female; D006084:Graft Rejection / Q000517:prevention & control; D006085:Graft Survival / Q000276:immunology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D016030:Kidney Transplantation / Q000276:immunology* / Q000379:methods; D008213:Lymphocyte Activation / Q000187:drug effects*; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D010835:Phytohemagglutinins / Q000494:pharmacology; D011239:Prednisolone / Q000494:pharmacology
chemical_list: D007166:Immunosuppressive Agents; D010835:Phytohemagglutinins; D016572:Cyclosporine; D011239:Prednisolone; D009173:Mycophenolic Acid; D001379:Azathioprine