EXPERIMENTAL AUTOIMMUNE GLOMERULONEPHRITIS (EAG) INDUCED BY HOMOLOGOUS AND HETEROLOGOUS GLOMERULAR-BASEMENT-MEMBRANE IN 2 SUBSTRAINS OF WISTAR-KYOTO RAT

Background. Goodpasture's, or antiglomerular basement membrane (GBM), disease presents with rapidly progressive glomerulonephritis, and is c aused by autoimmunity to the NC1 domain of the alpha 3 chain of type I V collagen. In order to investigate mechanisms involved in the inducti on and regulation of glomerulonephritis, experimental models of Goodpa sture's disease have been developed in the rat which share many charac teristics with the human disease. Induction of experimental autoimmune glomerulonephritis (EAG) involves immunization of susceptible strains with either heterologous or homologous GBM in FCA. However, pathologi cal changes have tended to be mild and/or variable, except in certain protocols using Wistar-Kyoto (WKY) rats. Methods. We studied the susce ptibility of inbred WKY rats from two different suppliers to the devel opment of EAG. These substrains of rat had different MHC haplotypes (W KY/CR, RT1-1; WKY/Olac, RT1-k), so we proposed that they might show di fferences in their immune response to GBM antigens. Both substrains we re immunized with sheep GBM, pH 7, or rat GBM buffered to pH 3, pH 5 o r pH 7. Results. All immunized rats developed circulating anti-GBM ant ibodies detectable at 14 days and rising until 28 days, at which time there was linear deposition of IgG on the GBM. WKY/CR rats developed s evere focal segmental proliferative and necrotizing glomerulonephritis , with heavy albuminuria, following immunization with rat GBM, pH 7, b ut only moderate disease following sheep GBM. WKY/Olac rats showed a m ore variable response, with moderate disease following both rat and sh eep GBM. Immunization of either substrain with rat GBM, pH 5, produced a response similar to that with rat GBM, pH 7, but disease was mild f ollowing rat GEM, pH 3. Conclusion, EAG in the WKY rat varies in sever ity according to the substrain of animal and preparation of GBM used f or immunization. The model with the most severe and consistent changes was that induced in the WKY/CR rat by rat GBM at pH 7. This model of EAG will be of value for investigating mechanisms of autoimmunity and inflammation in glomerulonephritis, and for attempting novel forms of immunotherapy prior to trials in man.