No abstract

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.

In order to study disease mechanisms and potential forms of therapy in glomerulonephritis, a model of experimental autoimmune glomerulonephritis (EAG) has been developed in the rat. We have examined the response of Brown-Norway (BN) rats to a single i.m. injection of collagenase-solubilised homologous (Sprague-Dawley, SD) or isologous (BN) glomerular basement membrane (GBM), with and without complete Freund's adjuvant (CFA). There was a dose-dependent circulating anti-GBM antibody response to all preparations of rat GBM. Animals given either antigen alone at a dose of 2 mg/kg developed circulating anti-GBM antibodies, which reached peak values by 6 weeks (63 +/- 5% following SD GBM; 53 +/- 8% following BN GBM), but did not develop glomerular deposits of IgG or nephritis. Animals given 2 mg/kg SD GBM in CFA developed greater concentrations of anti-GBM antibody by 6 weeks (122 +/- 20%) together with linear deposits of IgG on glomerular and tubular basement membranes (TBM), albuminuria (mean 7 mg/24 h), and variable focal segmental necrotising glomerulonephritis with mild interstitial nephritis. The same dose of BN GBM in CFA produced similar concentrations of circulating antibody (144 +/- 26%), with linear deposits of IgG on GBM but rarely TBM, little albuminuria, and variable mild focal glomerulonephritis. Other strains injected with SD GBM in CFA showed a variable circulating anti-GBM antibody response, which was similar to that of BN rats in PVG and DA rats but lower in LEW and WAG rats. Linear deposits of IgG on the GBM were detected in a proportion of PVG and DA rats, but not in LEW or WAG rats.(ABSTRACT TRUNCATED AT 250 WORDS)

The distribution of Goodpasture antigen (GA) was studied in a range of human tissues using indirect immunofluorescence and immunoperoxidase techniques. Frozen sections were stained using (1) a mouse monoclonal antibody (P1) raised against the autoantigenic component of human glomerular basement membrane, (2) autoantibodies eluted from the kidneys of patients with Goodpasture's syndrome, (3) antibodies eluted from the kidneys of a sheep with Steblay nephritis, and (4) mouse monoclonal and guinea pig polyclonal antibodies to human type IV collagen. The same pattern of staining was demonstrated using the eluted antibodies and monoclonal antibody P1. The presence of GA was confirmed in the lung and choroid plexus. GA was also detected in basement membranes at a number of previously unreported sites in the eye, thyroid, pituitary, adrenal, breast, and liver. GA was absent from other sites at which type IV collagen could be demonstrated. Direct immunofluorescence studies of tissue from a patient with Goodpasture's syndrome revealed deposition of IgG in the choroid plexus and eye, as well as in the kidney and lung.

SUMMARYGlomerular injury caused by injection of heterologous anti-glomerular basement membrane antibodies (anti-GBM Ab) is increased in rats pretreated with small doses of bacterial lipopolysaccharide (LPS). We have Investigated the involvement of tumour necrosis factor-alpha (TNF-a), IL-la and IL-l^in this phenomenon by passive immunization against these cytokines. Anti-TNF-«oranti-IL-l/i antibodies given 15 h before the induction of nephritis significantly decreased injury in this model, whether assessed by the magnitude of albuminuria. the prevalence of giomerular capillary thrombi or the intensity of glomerular neutrophil infiltrate. Aibuminuria in anti-GBM Ab alone was U ±3. LPS/anU-GBM Ab 87 + 22. and anti-TNF-a antibodies/LPS/anti-GBM Ab 21 ±6 mg/24 h (mean + s.e.) /*<0-05. Passiveimmunization with antibodies to IL-l/f had a similar effect (anti-GBM Ab.O-6 + 0-l,LPS/anti-GBM Ab.92+19.anti-IL-l/fantibodies/LPS./anti-GBM Ab39±8mg/24h. P<{)QS). The prevalence of glomerular capillary thrombi was also reduced significantly by these Ircatmcnts; from 22±5% to 4±1% in the case of anti-TNF-a antibodies and 28±5% to 13 ±4% with anti-IL-1 ^antibodies, Similarly, the glomerular neutrophil infiltrate was also reduced by these treatments; from 42 + 3 to 25±1 In the case of anti-TNF-D; and 47±2 to 30+1 with anti-IL-lâ ntibodies. In eontrast, passive immunization againsi IL-la had no effect on either albumin excretion {4 + 3, 83 + 22 and 77 + 24 mg/24 h), glomerular capillary thrombi (2+1; I9±5 and !6±3) or glomerular neutrophil infiltrate (22 + 3; 47 + 5 and 48 + 5 from the three groups respectively). These results demonstrate that enhanced antibody mediated injury in the kidney is modulated by TNF-a and \L-\(i but not by IL-la.Keywords nephrotoxic antibody lipopolysaccharide tumour necrosis factor-alpha interleukin-1 a and P aipha 2-macroglobulln