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Pharmacodynamics of Mycophenolate Mofetil after Heart Transplantation: New Mechanisms of Action and Correlations with Histologic Severity of Graft Rejection
Author(s) -
Barten Markus J.,
Van Gelder Teun,
Gummert Jan F.,
Boeke Katrin,
Shorthouse Randi,
Billingham Margaret E.,
Morris Randall E.
Publication year - 2002
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1034/j.1600-6143.2002.20806.x
Subject(s) - mycophenolate , medicine , mycophenolic acid , mixed lymphocyte reaction , lymphocyte , heart transplantation , pharmacodynamics , pharmacology , in vivo , immune system , whole blood , antigen , transplantation , immunology , pharmacokinetics , t cell , biology , microbiology and biotechnology
The primary mechanism of action in vivo of mycophenolate mofetil (MMF) is believed to be inhibition of lymphocyte proliferation. We used novel assays of lymphocyte functions (pharmacodynamics, PD) in whole blood collected from rat heart allograft recipients treated with MMF to investigate the mechanisms of action of the active metabolite of MMF, mycophenolate acid (MPA) in vivo . Allograft recipients were treated orally once daily with 3 different doses of MMF. Seven days after transplantation, blood was collected 24 h after the penultimate dose and several timepoints after the last dose, after which grafts were removed for microscopic grading of rejection. Lymphocytes in whole blood samples were mitogen stimulated through calcium‐dependent and ‐independent signaling pathways. Inhibition of PD was measured by lymphocyte proliferation and expression of several surface antigens on T cells, and was calculated as area under the time‐inhibition of immune function effect curve (AUE 0−24 h ). We found that inhibition of lymphocyte proliferation and antigen expression by MPA correlated highly with MMF‐dose, MPA level and with the histologic severities of graft rejection (p < 0.05). In summary, MPA suppressed lymphocyte proliferation and expression of T‐cell surface antigens in whole blood collected from MMF‐treated allograft recipients, thus demonstrating the multiple mechanisms of suppression of rejection on peripheral blood T cells after MMF treatment.