Leukocyte adhesion molecules: potential targets for therapeutic intervention in kidney diseases

Abstract

Neutrophils and monocytes (phagocytes) are important mediators of injury in many inflammatory diseases, including glomerulonephritis and vasculitis. Current treatment modalities (eg, corticosteroids, cytotoxic agents) are relatively nonspecific in their actions, frequently ineffective, and often associated with immunologic or metabolic complications. Recent advances in cellular and molecular immunobiology have suggested novel targets for therapeutic intervention. Phagocyte adhesion to endothelial cells, in particular, is a central event in the recruitment of phagocytes to sites of inflammation. Phagocyte trafficking to the extravascular space requires the coordinated interactions of several families of adhesion molecules, including the selectins, integrins, and immunoglobulin-like molecules. Initial attachment appears to be achieved by the interaction of phagocyte or endothelial cell selectins with carbohydrate-containing counter-receptors. These events facilitate immobilization of phagocytes via the interaction of phagocyte integrins with immunoglobulin-like molecules on endothelial cells and diapedesis to the extravascular tissue. Chemoattractants and cytokines regulate adhesion by altering the avidity or surface expression of preformed molecules and by influencing de novo synthesis of adhesion molecules. The intensity and composition of leukocyte infiltrates at sites of inflammation likely reflect the local balance of pro- and anti-inflammatory chemoattractants and cytokines and the profile of adhesion molecules on invading and resident cells. Adhesion may also promote tissue injury by augmenting phagocyte oxidative bursts and lysosomal enzyme release and by facilitating release of these cytotoxic molecules in close proximity to tissue cells. In addition, adhesion may amplify the levels and types of inflammatory mediators within a local milieu by promoting transcellular eicosanoid biosynthesis during cell-cell interaction. Increased adhesion molecule expression has been reported in glomerulonephritis, vasculitis, tubulointerstitial nephritis, transplant rejection, and hemodialysis "first-use" reactions. In addition, leukocyte adhesion may be an important event in the pathophysiology of ischemia-reperfusion injury. Monoclonal antibodies against adhesion molecules confer dramatic protection in several models of renal inflammation. Further studies in this area may yield potent and specific therapies for common renal diseases.