ABROGATION OF MERCURIC CHLORIDE-INDUCED NEPHRITIS IN THE BROWN-NORWAYRAT BY TREATMENT WITH ANTIBODIES AGAINST TNF-ALPHA

HgCl2 induces an ailtoimmune disease in the Brown Norway rat character ized by synthesis of autoantibodies (mainly, anti-GBM Abs), severe pro teinuria and interstitial nephritis. Also, HgCl2-injected rats develop glomerular cell infiltrates consisting of ED1(+) cells (monocyte/macr ophage), starting on day 4 and reaching a maximum on day 8. Treatment with anti-TNF-alpha antiserum had preventative effects as it reduced t he urinary protein levels to close to the normal range and also blocke d the influx of inflammatory cells in the renal glometull and intersti tium, but circulating anti-GBM and lineal glomerular IgG deposits were unmodified. In addition, whole isolated glomeruli from HgCl2-lnduced nephritis secreted TNF-alpha commencing on day 8, being maximally dete cted on day 11 and preceding, between 2 to 3 days, the development of proteinuria. The administration of anti-TNF-alpha antiserum or anti-al pha 4 integrin mAb completely abrogated the synthesis of TNF-alpha in glomeruli isolated from the respective treated groups of animals, in a ddition to the proteinuria. Taken together our results confirm that TN F-alpha plays an important role in the induction and development of Hg Cl2-induced nephritis and highlights the pathogenic importance ofthe l ocal release of TNF in those renal diseases in which prominent glomaul ar macrophage accumulation is a constant feature.