Nephrology Dialysis Transplantation, Vol 13, Issue 1 44-52, Copyright © 1998 by Oxford University Press
J Reynolds, K Mavromatidis, S Cashman, D Evans and C Pusey
Background: Goodpasture's or antiglomerular basement
membrane (GBM), disease presents with rapidly progressive
glomerulonephritis, and is caused by autoimmunity to the NCl domain of the
&agr;3 chain of type IV collagen. In order to investigate mechanisms
involved in the induction and regulation of glomerulonephritis,
experimental models of Goodpasture's disease have been developed in the rat
which share many characteristics with the human disease. Induction of
experimental autoimmune glomerulonephritis (EAG) involves immunization of
susceptible strains with either heterologous or homologous GBM in FCA.
However, pathological changes have tended to be mild and/or variable,
except in certain protocols using Wistar-Kyoto (WKY) rats.
Methods: We studied the susceptibility of inbred WKY
rats from two different suppliers to the development of EAG. These
substrains of rat had different MHC haplotypes (WKY/CR, RT1-1; WKY/Olac,
RT1-k), so we proposed that they might show differences in their immune
response to GBM antigens. Both substrains were immunized with sheep GBM,
pH7, or rat GBM buffered to pH 3, pH 5, or pH 7.
Results: All immunized rats developed circulating
anti-GBM antibodies 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 severe focal segmental proliferative and necrotizing
glomerulonephritis, with heavy albuminuria, following immunization with rat
GBM, pH 7, but only moderate disease following sheep GBM. WKY/Olac rats
showed a more variable response, with moderate disease following both rat
and sheep 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 following rat GBM, pH 3. Conclusion: EAG in the
WKY rat varies in severity according to the substrain of animal and
preparation of GBM used for 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. Key
words: autoimmunity; experimental autoimmune glomerulonephritis
(EAG); glomerular basement membrane (GBM); Goodpasture' disease;
Wistar-Kyoto (WKY) rat
ORIGINAL ARTICLES
Experimental autoimmune glomerulonephritis (EAG) induced by homologous and heterologous glomerular basement membrane in two substrains of Wistar-Kyoto rat
Renal Unit, Department of Medicine, Royal Postgraduate Medical School, Du Cane Road, London W12 0NN, UK; Department of Histopathology, St Mary's Hospital Medical School, London, UK; Corresponding author
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