Differing roles of CD18 and VLA-4 in leukocyte migration/activation during anti-GBM nephritis

Abstract

The mechanisms underlying leukocyte migration into inflamed glomeruli and their in situ activation are incompletely understood. We addressed this issue by investigating the effects of monoclonal antibodies (mAbs) to CD18 and VLA-4 on these process in the heterologous phase of anti-glomerular basement membrane (GBM) nephritis in rat. Anti-CD18 mAb substantially attenuated neutrophil (PMN) migration into glomeruli and the accompanying proteinuria which is a function of in situ leukocyte activation (ca. 60%). Anti-VLA-4 mAb modestly inhibited PMN migration (ca. 20%) and had no significant effect on proteinuria. Combination of both mAbs was no more effective than anti-CD18 mAb alone. Despite continued mAb blockade of CD18 or VLA-4 (or both), macrophage (M phi) migration following PMN influx was unaltered. However, combined CD18/VLA-4 mAbs diminished the proteinuria associated with M phi influx (ca. 50%). Abrogation of the acute influx of PMNs in this model (via complement depletion or anti-PMN antibody) did not diminish the following influx of M phi s, although the associated proteinuria was abolished. In this context, M phi migration was substantially decreased by anti-VLA-4 mAb (ca. 50%), but not anti-CD18 mAb (either alone or with anti-VLA-4 mAb). In sum, leukocyte migration and activation in the heterologous phase of anti-GBM nephritis are dependent on CD18 and VLA-4, although to varying degrees depending on the leukocyte subtype and the presence of prior inflammation. Nonetheless, a significant component of both PMN and M phi migration/activation is CD18/VLA-4 independent.