β2 Integrin independent neutrophil recruitment and injury in anti‐GBM glomerulonephritis in rabbits

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Abstract
The role of the 2 integrin cell adhesion molecules (CAM) in directing neutrophil accumulation and injury in acute anti-glomerular basement membrane antibody induced glomerulonephritis (anti-GBM GN) was assessed in rabbits by in vivo inhibition of CD 18 dependent neutrophil/endothelial cell interactions using a monoclonal anti-CD 18 antibody. Rabbits given horse anti-rabbit GBM antibody developed significant glomerular neutrophil influx (2.9 0.1 neutrophils per glomerular cross-section [c/gcs], normal 0.1 0.1 c/gcs, P = 0.002) and proteinuria (1389 257 mg/16 h, normal 15 4mg/16 h, P = 0.0015) after 16 h. Rabbits rendered neutropenic (< 500 neutrophils/L) by mustine hydrochloride, or complement depleted by cobra venom factor, did not develop glomerular neutrophil accumulation and had markedly reduced proteinuria after anti-GBM antibody, demonstrating complement-induced neutrophil recruitment is a major mechanism of glomerular injury in this model. Anti-CD 18 antibody treatment of rabbits developing anti-GBM GN abrogated dermal neutrophil influx in response to intradermal injection of fMLP and zymosan activated serum. Treated rabbits achieved levels of anti-CD 18 antibody in their serum which saturated the binding sites on rabbit neutrophils in vitro, and their circulating neutrophils had saturated anti-CD 18 antibody binding in vivo. However, glomerular neutrophil influx (3.5 0.4 c/gcs) and proteinuria (1210 428 mg/16 h) were both unaffected. Thus, in this model of antibody-initiated complement and neutrophil-dependent glomerular injury, in which neutrophil transmigration across the endothelium is not required, effective functional inhibition of 2 integrin CAM in vivo did not reduce glomerular injury or glomerular neutrophil influx. These studies demonstrate that 2 integrin CAM are not a requirement for neutrophil accumulation and glomerular injury in anti-GBM GN in rabbits.