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Mycophenolate mofetil reduces production of interferon-dependent major histocompatibility complex induction during allograft rejection, probably by limiting clonal expansion.
Lui, S L; Ramassar, V; Urmson, J; Halloran, P F.
Afiliação
  • Lui SL; Department of Medicine, University of Alberta, Edmonton.
Transpl Immunol ; 6(1): 23-32, 1998 Mar.
Article em En | MEDLINE | ID: mdl-9640625
The immunosuppressive drug mycophenolate mofetil (MMF) acts by releasing mycophenolic acid (MPA), which inhibits the enzyme inosine monophosphate dehydrogenase (IMPDH) and thus inhibits de novo purine synthesis. Unlike cyclosporine (CsA), MMF has no direct effect on cytokine gene expression in vitro. We examined the effect of MMF, in comparison to CsA, on in vivo production of interferon-gamma (IFN-gamma) in mice. Two stimuli for IFN-gamma induction were used: (1) allogeneic P815 mastocytoma ascites tumour cells and (2) bacterial lipopolysaccharide (LPS). The allogeneic response is dependent on clonal expansion of T cells, while the LPS response is polyclonal and T cell independent. Since major histocompatibility complex (MHC) induction in mouse kidney is IFN-gamma dependent, we assessed the in vivo induction of IFN-gamma indirectly by measuring MHC induction in mouse kidneys in three systems: radiolabelled antibody binding assay, immunoperoxidase staining in tissue sections, and Northern blotting for steady-state MHC mRNA levels. IFN-gamma steady-state mRNA levels were assessed by reverse transcriptase polymerase chain reaction (RT-PCR). In the allogeneic response, MMF (40-160 mg/kg/day) reduced the production of IFN-gamma in a dose-dependent fashion. MHC class I and II induction was reduced by 35% to 74% and 30% to 74%, respectively. However, MMF had less effect on the induction of MHC by a nonimmune stimulus, bacterial LPS, whereas CsA reduced the induction of IFN-gamma in both responses. We conclude that MMF reduces the IFN-dependent induction of MHC in vivo during specific immune responses, probably by limiting clonal expansion, while preserving nonspecific cytokine production in response to LPS.
Assuntos
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Base de dados: MEDLINE Assunto principal: Imunologia de Transplantes / Antígenos de Histocompatibilidade Classe I / Antígenos de Histocompatibilidade Classe II / Interferon gama / Rejeição de Enxerto / Imunossupressores / Ácido Micofenólico Limite: Animals Idioma: En Ano de publicação: 1998 Tipo de documento: Article
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Base de dados: MEDLINE Assunto principal: Imunologia de Transplantes / Antígenos de Histocompatibilidade Classe I / Antígenos de Histocompatibilidade Classe II / Interferon gama / Rejeição de Enxerto / Imunossupressores / Ácido Micofenólico Limite: Animals Idioma: En Ano de publicação: 1998 Tipo de documento: Article