Apoptosis of superantigen-activated T cells induced by mycophenolate mofetil treatment.
BACKGROUND
Mycophenolate mofetil (MMF), an ester prodrug of mycophenolic acid (MPA), is a potent immunosuppressive agent used in clinical organ transplantation. MPA preferentially inhibits the type II isoform of inosine monophosphate dehydrogenase, depletes GTP, suppresses transfer of mannose and fucose to glycoproteins, and prevents lymphocyte proliferation in vivo. Whether MMF can also delete activated T cells in vivo by triggering an apoptotic signal was addressed in this study. To this end we analyzed the activity of MMF in mice injected with the bacterial superantigen staphylococcal enterotoxin B (SEB). Superantigens bind to MHC class II molecules without requirement for processing, and activate subsets of CD4+ and CD8+ T cells whose T cell receptor beta chains express Vbeta family-specific homologous sequences. This model that shares several features with direct allorecognition has the unique advantage of allowing a precise monitoring of activated T cells.


METHODS
BALB/c mice treated with MMF (100 mg/kg/ day) or vehicle were injected with SEB. Serum cytokines, CD4+ and CD8+ Vbeta8+ cells were monitored in blood and lymphoid tissues, and apoptosis was determined by externalization of membrane phosphatidyl serine, double strand DNA breaks, and expression of B220 antigen by Vbeta8+ cells.


RESULTS
MMF treatment decreased tumor necrosis factor alpha, interferon gamma, and interleukin-10 secretion induced by SEB. It did not modify other early activation events (blast transformation, CD69 and CD25 expression) but completely inhibited SEB-induced expansion of Vbeta8+ cells by inducing apoptosis of SEB-reactive T cells. A similar effect was observed in CD95-ligand-deficient mice. Repeated SEB injections associated with MMF resulted in a marked decrease of CD8+ Vbeta8+ T cells. SEB-induced increase of Vbeta8+ thymocytes was not prevented by MMF treatment.


CONCLUSIONS
Results obtained in this in vivo model suggest that MMF treatment may induce deletion of activated peripheral T cells and decrease early cytokine responses.
Izeradjene
K
K
Laboratory of Immunopharmacology, Institut National de la Santé et de la Recherche Médicale U 503, Claude Bernard University, Hopital E Herriot, Lyon, France.
Revillard
J P
JP
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis / Q000187:drug effects; D004768:Enterotoxins / Q000494:pharmacology*; D053222:Fas Ligand Protein; D008213:Lymphocyte Activation / Q000276:immunology; D008212:Lymphocyte Depletion; D008562:Membrane Glycoproteins / Q000172:deficiency; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D018089:Superantigens / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology*
D016207:Cytokines; D004768:Enterotoxins; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D018089:Superantigens; C031818:enterotoxin B, staphylococcal; D009173:Mycophenolic Acid