MYCOPHENOLATE-MOFETIL PREVENTS THE INDUCTION OF ACTIVE HEYMANN NEPHRITIS - ASSOCIATION WITH TH2 CYTOKINE INHIBITION

The effect of mycophenolate mofetil (MMF) was examined in active Heyma nn 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 wa s not different in CFA controls up to 16 wk, and was significantly les s than in untreated HN from 6 wk onward. Serum anti-Fx1A antibody (Ab) levels and glomerular Ig deposition were suppressed during therapy. T he interstitial infiltrate of alpha beta TCR+, CD4(+) and CD8(+) T cel ls, natural killer cells, and macrophages (m phi) observed in untreate d HN at 8 wk was absent from rats treated from 0 to 4 wk with MMF. Sem iquantitative reverse transcription-PCR for renal mononuclear cell cyt okine mRNA at 8 wk demonstrated that MMF from 0 to 4 wk prevented the increased expression of Th1 (interferon-gamma, lymphotoxin), Th2 (inte rleukin-LC), and m phi (tumor necrosis factor-alpha) cytokines identif ied 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, lymphoto xin) 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 g lomerular IgG deposition when compared with untreated ITN. This study showed that MMF from 0 to 4 wk prevented the induction of HN and was a ssociated with preferential suppression of Th2 cytokines. This therapy may prove useful in human idiopathic membranous nephropathy.