Antibodies to intercellular adhesion molecule 1/lymphocyte function-associated antigen 1 prevent crescent formation in rat autoimmune glomerulonephritis.

Abstract

SBmlTlftryIn 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 oL3 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. In addition, in rats in which treatment was started after onset of the disease, the titers of anti-GBM antibodies did not decrease, although the progression of disease was inhibited. We conclude that the preventive or therapeutic effects of antibodies to ICAM-1 and LFA-1 in rat anti-GBM glomerulonephritis probably resulted mainly from interference with interaction between leukocytes and activated glomerular endothelium, although reduction in the autoimmune response may have contributed to the beneficial effects. The res...

IL-18 Has IL-12-Independent Effects in Delayed-Type Hypersensitivity: Studies in Cell-Mediated Crescentic Glomerulonephritis

“…IL-12 administration, or the absence of endogenous IL-4 or IL-10, enhances renal injury and crescentic GN (22,25,26). The relevance of adhesion molecules and chemokines in this model has been demonstrated by studies showing that severe injury and crescent formation in this and similar models are ICAM-1 and monocyte chemoattractant protein-1 dependent (27)(28)(29). Therefore, this model of crescentic glomerular injury provides a relevant and appropriate tool with which to study the IL-12-independent role of IL-18 in vivo.…”

“…The relevance of a number of adhesion molecules and chemokines has been demonstrated in crescentic glomerulonephritis (27)(28)(29) and dermal DTH (11)(12)(13). In the absence of any demonstrable effect by IL-18 in IL-12 Ϫ/Ϫ on proinflammatory cytokines such as IFN-␥, GM-CSF, and TNF-␣, the expression of the adhesion molecule ICAM-1 was studied within glomeruli.…”

Glomerulopathy Induced by Immunization with a Peptide Derived from the Goodpasture Antigen α3IV-NC1

“…Anti-GBM GN has been studied in a number of animal models using immunizations with heterologous or homologous GBM preparations or a3IV-NC1 to breach tolerance against the autoantigen, often referred to as experimental autoimmune GN (EAG) (10)(11)(12)(13). We have previously characterized the T cell response to heterologous human a3IV-NC1 in DBA/1 mice and found a biphasic disease course.…”

Effective treatment of experimental lupus nephritis by combined administration of anti-CD11a and anti-CD54 antibodies

“…Therefore, by treating with antibodies blocking both CD11a and CD54 activity, we may have affected more adhesion pathways than just the CD11a/CD54 ligand interaction. Many studies have shown that treatment with both anti-CD54 and anti-CD11a MoAbs is more effective than treatment with either MoAb alone [5,6,11,28,29,50], thus showing that the CD11a/CD54 interaction plays the most prominent functional role in these cell adhesion pathways. Additionally, as reviewed elsewhere [31,32,56], several other adhesion molecules contribute significantly in interactions between lymphocytes and in the adhesion of leucocytes to damaged tissues.…”

“…Combined treatment with anti-CD11a/anti-CD54 MoAbs was more effective than treatment with either of these antibodies alone [5,6]. These studies were performed in acute models for the organ-specific autoimmune disease anti-glomerular basement membrane (GBM) glomerulonephritis.…”