Anti-Inflammatory Effects of αv Integrin Antagonism in Acute Kidney Allograft Rejection

Integrin-mediated cell adhesion and signaling is essential to vascular development and inflammatory processes. Elevated expression of integrin αvβ3 has been detected in ischemia-reperfusion injury and rejecting heart allografts. We thus hypothesized that the inhibition of αv-associated integrins may have potent anti-inflammatory effects in acute kidney allograft rejection. We studied the effects of a peptidomimetic antagonist of αv integrins in two rat models of renal allotransplantation, differing in degree of major histocompatibility complex mismatch. Integrin αvβ3 was up-regulated in rejecting renal allografts. Integrin antagonist reduced the histological signs of acute rejection, the intensity of the mononuclear cell infiltration, and cell proliferation in the grafted kidneys. This could be correlated to a reduced leukocyte-endothelial interaction and an improved peritubular microcirculation observed by intravital microscopy. In vitro under laminar flow conditions, the arrest of monocytes to interleukin-1β-activated endothelium was decreased. Furthermore, in co-culture models the proliferation and transmigration of monocytes/macrophages, endothelium, and fibroblasts induced by renal tubular epithelia was efficiently inhibited by αv integrin antagonism. These data reveal an important role of this integrin subclass in leukocyte recruitment and development and maintenance of acute rejection; blockade of αv integrins may provide a new therapeutic strategy to attenuate acute allograft rejection.