Lymphocyte‐Selective Cytostatic and Immunosuppressive Effects of Mycophenolic Acid in Vitro: Role of Deoxyguanosine Nucleotide Depletion

Abstract

Mycophenolic acid (MPA), an inhibitor of inosine monophosphate dehydrogenase, in nanomolar concentrations blocks proliferative responses of cultured human, mouse and rat T lymphocytes and B lymphocytes to mitogens or in mixed lymphocyte reactions. The inhibitory effect of MPA on lymphocyte proliferation is reversed by addition to culture media of deoxyguanosine or guanosine but not by addition of deoxyadenosine or adenosine. The findings suggest that the principal mechanism of action of low concentrations of MPA is depletion of deoxyguanosine triphosphate which is required for DNA synthesis. In immunosuppressive doses, MPA does not affect the formation of IL-1 by LPS-activated human peripheral blood monocytes. Unlike cyclosporin A and FK-506, MPA does not inhibit the formation of IL-2 and the expression of the IL-2 receptor in mitogen-activated human T lymphocytes. MPA suppresses mixed lymphocyte reactions when added 3 days after their initiation. These findings suggest that MPA does not inhibit early responses of T and B lymphocytes to mitogenic or antigenic stimulation but blocks the cells at the time of DNA synthesis. The cytostatic effect of MPA is more potent on lymphocytes than on other cell types, such as fibroblasts and endothelial cells. MPA also inhibits antibody formation by polyclonally activated human B lymphocytes. MPA is an immunosuppressive agent reversibly inhibiting proliferation of T and B lymphocytes and antibody formation, with a profile of activity different from that of other immunosuppressive drugs. Human T and B lymphocytic and promonocytic cell lines are highly sensitive to the antiproliferative effects of MPA, whereas the erythroid precursor cell line K562 is less susceptible. The effect of MPA on cells of the monocyte-macrophage lineage could exert long-acting anti-inflammatory activity. MPA or analogues may have therapeutic utility in diseases such as rheumatoid arthritis, for prevention of allograft rejection and in lymphocytic or monocytic leukaemias and lymphomas.

Effect of adding Mycophenolate mofetil in paediatric renal transplant recipients with chronical cyclosporine nephrotoxicity

“…Apart from the more intense immunosuppressive action compared to that of Aza, MMF has also been associated with a better tolerability in patients with hepatitis [22,351 showing a possible virostatic effect [l], and has also been claimed to be an antiproliferative agent [6], possibly reducing progression of renal insufficiency. Indeed, there was an improvement of serum creatinine in all our patients and no patient progressed into renal failure.…”

Mycophenolate Mofetil versus Azathioprine in the Maintenance Therapy of Lupus Nephritis

“…Mycophenolic acid (MPA), the active metabolite of MMF, is an inhibitor of the crucial enzyme involved in the de novo synthesis of guanosine nucleotides. [5,6] As lymphocytes do not possess a salvage pathway for the generation of these nucleotides, MMF results in selective blockade of B-and T-cell proliferation. Unlike CYC, MPA has little impact on other tissues with high proliferative activity, which possess a salvage pathway for nucleotide synthesis.…”

Nephrotic Syndrome: Past, Present and Future

“…Активным началом мофетила микофенолата является микофеноловая кислота, которая ингибиру-ет инозин монофосфат дегидрогеназу и предупреж-дает de novo синтез гуанозина и деоксигуанозина в лимфоцитах. Этим путем достигается блокада про-лиферации Т-и В-лимфоцитов и тем самым пода-вление продукции антител и генерации цитотокси-ческих клеток [50]. Существуют экспериментальные данные, говорящие о ренопротективном влиянии мофетила микофенолата за счет подавления цитоки-ниндуцирующей продукции NO и снижения проли-ферации гломерулярного и тубулярного матрикса [51].…”