title: Mycophenolic acid inhibits natural killer cell proliferation and cytotoxic function: a possible disadvantage of including mycophenolate mofetil in the graft-versus-host disease prophylaxis regimen.
abstract: To determine how immunosuppressant agents used for graft-versus-host disease (GVHD) prophylaxis affect natural killer (NK) cells, we examined the effects of cyclosporine (CSP), tacrolimus (TAC), mycophenolic acid (MPA, an active form of mycophenolate mofetil), and methotrexate (MTX) on the proliferation and cytotoxicity of NK cells. The proliferation of NK cells from healthy individuals in the presence of interleukin (IL)-2 and IL-15 was suppressed to 51% ± 16% of that of the controls with CSP, to 31% ± 19% with TAC, to 14% ± 6% with MPA, and to 87% ± 18% with MTX. Both CSP and TAC increased the proportion of CD16(-)CD56(bright) cells, a NK cell subset capable of secreting high amount of cytokines, and also enhanced NKp30 expression, whereas MPA markedly decreased the proportion of CD16(-)CD56(bright) cells and reduced the expression of all activating NK cell receptors, including NKG2D, NKp30, NKp44, and NKp46. MPA also reduced the cytotoxicity against K562 cells from 61% ± 15% to 17% ± 7% and that against Daudi cells from 44% ± 4% to 4% ± 4%, whereas the other 3 drugs did not diminish these cytotoxicities. The inhibition of NK cell proliferation and cytotoxicity against leukemic cell lines by MPA was partially abolished by the inclusion of guanosine in the culture. Similar to the effect of MPA on T cells, MPA inhibited the down-regulation of p27 on NK cells induced by the incubation of NK cells in the presence of IL-2. These results suggest that MPA is a potent inhibitor of NK cells, and that its inclusion in the GVHD prophylaxis regimen might diminish the graft-versus-leukemia effect of NK cells.
authors.affiliation: Cellular Transplantation Biology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.
authors.forename: Kinya
authors.initials: K
authors.lastname: Ohata
authors.forename: J Luis
authors.initials: JL
authors.lastname: Espinoza
authors.forename: Xuzhang
authors.initials: X
authors.lastname: Lu
authors.forename: Yukio
authors.initials: Y
authors.lastname: Kondo
authors.forename: Shinji
authors.initials: S
authors.lastname: Nakao
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D050760:Cyclin-Dependent Kinase Inhibitor p27; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006086:Graft vs Host Disease / Q000517:prevention & control; D020544:Graft vs Leukemia Effect / Q000187:drug effects; D006151:Guanosine / Q000378:metabolism; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D015979:Killer Cells, Lymphokine-Activated / Q000187:drug effects* / Q000502:physiology*; D008213:Lymphocyte Activation / Q000187:drug effects; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000494:pharmacology* / Q000627:therapeutic use; D011355:Prodrugs / Q000627:therapeutic use; D055607:Receptors, Natural Killer Cell / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000378:metabolism
chemical_list: C436291:CDKN1B protein, human; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D047908:Intracellular Signaling Peptides and Proteins; D011355:Prodrugs; D055607:Receptors, Natural Killer Cell; D006151:Guanosine; D050760:Cyclin-Dependent Kinase Inhibitor p27; D007168:IMP Dehydrogenase; D009173:Mycophenolic Acid