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Positive effect on T‐cell regulatory apoptosis by mycophenolate mofetil
Author(s) -
Nakamura M.,
Ogawa N.,
Shalabi A.,
Maley W. R.,
Burdick J. F.
Publication year - 2001
Publication title -
clinical transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.918
H-Index - 76
eISSN - 1399-0012
pISSN - 0902-0063
DOI - 10.1034/j.1399-0012.2001.00006.x
Subject(s) - calcineurin , apoptosis , ionomycin , medicine , annexin , fas ligand , cd28 , cd3 , microbiology and biotechnology , mycophenolic acid , t cell , flow cytometry , immunology , pharmacology , programmed cell death , transplantation , stimulation , andrology , immune system , biology , endocrinology , cd8 , biochemistry
The regulatory benefit of apoptosis (activation‐induced cell death, AICD) in T cells may be impacted by immunosuppressive agents. We examined this for mycophenolate mofetil (MMF) compared with cyclosporine (CYA). Peripheral blood leukocytes (PBL) were stimulated by either Staph enterotoxin B (SEB) or by anti‐CD3 plus anti‐CD28. Cell division analysis (sequential reduction in carboxyflourescein diacetate succinimidyl ester, CFSE) was used to measure proliferation and determine status of different cell generations. Apoptosis was measured by annexin V staining, and FasL expression by anti‐FasL antibody staining, of activated cells using flow cytometry. CSA and mycophenolic acid (MPA, the active agent of MMF) were added in titration in 3‐day cultures. We found that CSA caused diminution in apoptosis but MPA increased it with SEB stimulation. The CSA effect on apoptosis was present when a more calcineurin‐dependent stimulus, anti‐CD3+anti‐CD28, was used but the MPA effect was less, producing a decrease only in the undivided cells. To look more directly at the differential effect on calcineurin‐dependent AICD gene induction of the two agents, we measured Fas‐L expression with anti‐CD‐3+CD28 stimulation, and confirmed that CYA caused a major decrement in appearance of Fas‐L, whereas MPA caused a converse accumulation of it. This seems to be explained by the block more distal in cell activation, resulting in a build‐up of a precursor in the activation pathways. We conclude that MMF treatment may be rationale as an adjunct to calcineurin inhibitor treatment because of its converse effect on T cell regulatory apoptosis.