Related Experiment Videos
Antibodies to intercellular adhesion molecule 1/lymphocyte function-associated antigen 1 prevent crescent formation
K Nishikawa1, Y J Guo, M Miyasaka
1Department of Pathology, Massachusetts General Hospital, Boston.
Insights
Targeting intercellular adhesion molecule 1 (ICAM-1) and lymphocyte function-associated antigen 1 (LFA-1) with monoclonal antibodies significantly reduced crescentic glomerulonephritis severity in rats. Early intervention prevented glomerular damage and preserved renal function, showing therapeutic potential.
Area of Science:
- Nephrology
- Immunology
- Pathology
Background:
- Widespread crescents in glomerulonephritis correlate with poor prognosis.
- Crescent formation involves leukocyte migration into Bowman's space, highlighting leukocyte-endothelial interactions.
- Intercellular adhesion molecule 1 (ICAM-1) and lymphocyte function-associated antigen 1 (LFA-1) are key adhesion molecules in leukocyte trafficking.
Purpose of the Study:
- To investigate the therapeutic effects of monoclonal antibodies against ICAM-1 and LFA-1.
- To evaluate the impact of these antibodies on a rat model of crescentic glomerulonephritis induced by bovine glomerular basement membrane (GBM) immunization.
Main Methods:
- Induction of crescentic glomerulonephritis in Wistar-Kyoto rats via GBM immunization.
- Administration of monoclonal antibodies targeting rat ICAM-1 and LFA-1 at different time points (pre-immunization, early post-immunization, and later post-immunization).
- Assessment of renal pathology, proteinuria, glomerular immunoglobulin deposition, immune cell infiltration, and renal function.
Main Results:
- Antibody treatment significantly reduced glomerular abnormalities, proteinuria, and crescent formation.
- Early and continuous treatment (days -2 to 5 weeks) preserved normal renal function and virtually eliminated crescents.
- Delayed treatment (starting day 14) retarded disease progression and inhibited the decline in renal function.
Conclusions:
- Blocking ICAM-1 and LFA-1 interactions is a promising therapeutic strategy for crescentic glomerulonephritis.
- Early intervention with anti-ICAM-1 and anti-LFA-1 antibodies can prevent severe renal damage.
- These adhesion molecules play a critical role in the pathogenesis of this kidney disease.
Abstract:
In patients with glomerulonephritis widespread crescents are associated with a poor prognosis. Crescent formation appears to depend on the migration of mononuclear cells into Bowman's space, and therefore the interaction between leukocytes and glomerular endothelium may be a critical event in the genesis of crescents. We performed the present study to determine the effects of mouse monoclonal antibodies to the adhesion molecules intercellular adhesion molecule 1 (ICAM-1) and lymphocyte function-associated antigen 1 (LFA-1) in a model of crescentic glomerulonephritis in Wistar-Kyoto rats, induced by immunization with bovine glomerular basement membrane (GBM). By 10-14 d after immunization, the rats had developed circulating anti-GBM antibodies, reactive with the alpha 3 chain of type IV collagen (the Goodpasture antigen), accompanied by proteinuria, accumulation of rat immunoglobulin (Ig)G in the GBM, increased expression of ICAM-1 by glomerular endothelial cells, infiltration of glomerular tufts with LFA-1+ T cells and monocyte/macrophages, and early crescents. At 5 wk all rats had diffuse fibrocellular crescents, glomerular sclerosis, and tubulointerstitial damage. All rats developed severe renal insufficiency and died by 5 or 6 wk. The administration of monoclonal antibodies to rat ICAM-1 and LFA-1 markedly decreased the severity of the renal disease. In a group of rats injected three times a week with the monoclonal antibodies, from 2 d before immunization with GBM to day 14, glomerular abnormalities and proteinuria were virtually absent at day 14; even at 5 wk glomerular disease was quite mild, with only slight crescent formation and with only a mild decrease in renal function. When treatment was continued until 5 wk, the beneficial effects were even more marked, with virtual absence of crescents and with preservation of normal renal function. In a group of rats in which treatment was initiated on day 14, shortly after the appearance of glomerular abnormalities, progression of the disease was appreciably retarded, and the decrease in renal function was inhibited. The kidneys of rats treated from days -2 to 14 with antibodies to ICAM-1 and LFA-1 showed bright linear staining for rat IgG along the GBM, which did not differ in intensity from that seen in untreated rats. Furthermore, the titers of anti-GBM antibodies at 2 wk in treated rats were not lower than that seen in most of the untreated rats. There was, however, moderate reduction of anti-GBM antibodies at 5 wk in the treated rats.(ABSTRACT TRUNCATED AT 400 WORDS)