Ex vivo lymphocyte proliferative function is severely inhibited in renal transplant patients on mycophenolate mofetil treatment
Hutchinson, P and Jose, MD and Atkins, RC and Holdsworth, SR, Ex vivo lymphocyte proliferative function is severely inhibited in renal transplant patients on mycophenolate mofetil treatment, Transplant Immunology, 13, (1) pp. 55-61. ISSN 0966-3274 (2004) [Refereed Article]
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.