title: Mycophenolate mofetil prevents the induction of active Heymann nephritis: association with Th2 cytokine inhibition.
abstract: The effect of mycophenolate mofetil (MMF) was examined in active Heymann nephritis (HN), an animal model of human membranous nephropathy. HN was induced in Lewis rats with Fx1A/complete Freund's adjuvant (CFA), and controls only received CFA. The induction of HN was prevented by MMF (30 mg/kg per d) from 0 to 4 wk after immunization. Proteinuria was not different in CFA controls up to 16 wk, and was significantly less than in untreated HN from 6 wk onward. Serum anti-Fx1A antibody (Ab) levels and glomerular Ig deposition were suppressed during therapy. The interstitial infiltrate of alphabetaTCR+, CD4+ and CD8+ T cells, natural killer cells, and macrophages (mphi) observed in untreated HN at 8 wk was absent from rats treated from 0 to 4 wk with MMF. Semiquantitative reverse transcription-PCR for renal mononuclear cell cytokine mRNA at 8 wk demonstrated that MMF from 0 to 4 wk prevented the increased expression of Th1 (interferon-gamma, lymphotoxin), Th2 (interleukin-4), and mphi (tumor necrosis factor-alpha) cytokines identified in untreated HN. In lymph node draining sites of immunization, MMF limited both enlargement and the increased proportion of CD3+, CD4+, and CD8+ T cells observed in untreated HN and CFA controls. MMF suppressed Th2 (interleukin-4) but not Th1 (interferon-gamma, lymphotoxin) cytokine mRNA expression in lymph nodes. MMF from 4 to 8, 6 to 12, or 10 to 14 wk did not prevent proteinuria, serum anti-Fx1A Ab, or glomerular IgG deposition when compared with untreated HN. This study showed that MMF from 0 to 4 wk prevented the induction of HN and was associated with preferential suppression of Th2 cytokines. This therapy may prove useful in human idiopathic membranous nephropathy.
authors.affiliation: Department of Medicine, Liverpool Hospital and the University of New South Wales, Australia.
authors.forename: M J
authors.initials: MJ
authors.lastname: Penny
authors.forename: R A
authors.initials: RA
authors.lastname: Boyd
authors.forename: B M
authors.initials: BM
authors.lastname: Hall
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005921:Glomerulonephritis / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology / Q000517:prevention & control*; D015433:Glomerulonephritis, Membranous / Q000188:drug therapy / Q000276:immunology / Q000517:prevention & control; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics; D007378:Interleukins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D007672:Kidney Cortex / Q000276:immunology / Q000473:pathology; D008222:Lymphokines / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D008297:Male; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D011507:Proteinuria / Q000209:etiology / Q000517:prevention & control; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D011917:Rats, Inbred Lew; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism
chemical_list: D007378:Interleukins; D008222:Lymphokines; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D009173:Mycophenolic Acid