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Effects of Mycophenolate Mofetil in Mercury-Induced Autoimmune Nephritis

Elena Nieto^*, Esther Escudero^*, Elena Navarro^*, María Yáñez-Mo, Ana Martín, Guillermo Pérez de Lema, Francisco Sánchez-Madrid and Francisco Mampaso^*

*Department of Pathology, Hospital Ramón y Cajal, Universidad de Alcalá, Madrid, Spain; Department of Biology, Universidad SEK, Segovia, Spain; Klinische Biochemie, Medizinische Poliklinik der Ludwig-Maximiliams-Universitä, Munich, Germany; and Department of Immunology, Hospital La Princesa, Universidad Autónoma, Madrid. Spain.

Correspondence to: Dr. Francisco Mampaso, Department of Pathology, Hospital Ramon y Cajal, Carretera Colmenar km 9.100, Madrid 28034, Spain. Phone: 3413368052; Fax: 3413369016; E-mail: fmampaso{at}hrc.insalud.es

ABSTRACT. Mycophenolate mofetil (MMF) is a new immunosuppressive drug whose active metabolite, mycophenolic acid (MPA), blocks the action of inosine monophosphate dehydrogenase, resulting in the inhibition of the novo purine synthesis. Thus, MPA has an antiproliferative effect on T and B lymphocytes and also inhibits the glycosylation of cell surface adhesion proteins involved in cell-cell contact and in the recruitment of circulating leukocytes to sites of tissue damage and inflammation. In this study, the effect of MMF in the mercury model of nephritis was examined. Repeated exposure to HgCl₂ induces an autoreactive Th2 cell subset-inducing polyclonal B cell activation in the Brown Norway (BN) rat. This leads to the development of an autoimmune syndrome characterized by synthesis of autoantibodies (mainly anti–glomerular basement membrane [GBM] Abs) with glomerular linear deposits of IgG, proteinuria, and tubulointerstitial nephritis. Results show that MMF has a preventive effect on mercury-induced disease as it blocks anti-GBM Ab synthesis, thus avoiding glomerular IgG deposits and proteinuria and the development of interstitial nephritis. However, the therapeutic effect of MMF seems to be restricted to its antiinflammatory properties blocking the extravasation of circulating leukocytes to renal interstitium by interfering with the very late activation antigen 4/vascular cell adhesion molecule–1 (VCAM-1) cell adhesion pathway. Also, MMF administration to mercury-injected rats reduces the secretion of the proinflammatory cytokine tumor necrosis factor–. These findings confirm that MMF has a strong effect on the primary immune response in this model. Nevertheless, when the disease is in progress, MMF acts exclusively on the inflammatory response. MMF could be useful in the treatment of diseases associated with renal inflammation.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673