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Published online before print August 16, 2007
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Copyright © 2007 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2007.070329

Accepted for publication July 3, 2007.

Article

Anti-Inflammatory Effects of {alpha}v Integrin Antagonism in Acute Kidney Allograft Rejection

Jens Bedke*{dagger}, Eva Kiss*, Carl-Ludwig Behnes*, Zoran V. Popovic*, Markus Heuser{ddagger}, Tomislav Stojanovic{ddagger}, Tjeerd Sijmonsma*, Peter Huber{sect}, Sophie Domhan, Stefan Muschal{sect}, Amir Abdollahi{sect}||, Norbert Gretz**, and Hermann-Josef Gröne*@

From the Departments of Cellular and Molecular Pathology,* and Radiation Therapy,{sect} German Cancer Research Center, Heidelberg, Germany; the Departments of Urology,{dagger} and Nephrology, and the Medical Research Center, Klinikum Mannheim,** University of Heidelberg, Heidelberg, Germany; the Departments of Urology and Thoracic, Heart, and Vascular Surgery,{ddagger} Georg-August-University, Göttingen, Germany; and the Department of Medicine,|| Center of Cancer Systems Biology, Caritas Saint Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Massachusetts

@ To whom correspondence should be addressed. E-mail: h.-j.groene{at}dkfz.de.


  Abstract

Integrin-mediated cell adhesion and signaling is essential to vascular development and inflammatory processes. Elevated expression of integrin {alpha}v{beta}3 has been detected in ischemia-reperfusion injury and rejecting heart allografts. We thus hypothesized that the inhibition of {alpha}v-associated integrins may have potent anti-inflammatory effects in acute kidney allograft rejection. We studied the effects of a peptidomimetic antagonist of {alpha}v integrins in two rat models of renal allotransplantation, differing in degree of major histocompatibility complex mismatch. Integrin {alpha}v{beta}3 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-1{beta}-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 {alpha}v integrin antagonism. These data reveal an important role of this integrin subclass in leukocyte recruitment and development and maintenance of acute rejection; blockade of {alpha}v integrins may provide a new therapeutic strategy to attenuate acute allograft rejection.






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Copyright © 2007 by the American Society for Investigative Pathology.