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* German Cancer Research Center, Department of Experimental Pathology, Germany;
# Internal Medicine University of Utrecht, Netherlands;
Institute for Prophylaxis and Epidemiology, Ludwig-Maximilians-University of Munich, Germany;
§ Medical Policlinic, Ludwig-Maximilians-University of Munich, Germany; and
|| Serono Pharmaceutical Institute, Geneva, Switzerland
1Correspondence: Medizinische Poliklinik der Ludwig-Maximilians-Universität München, AG Klinische Biochemie, Schillerstrasse 42, D-80336, Munich, Germany. E-mail: nelson{at}medpoli.med.uni-muenchen.de
Chemokines are thought to contribute to the cellular infiltrate characteristic of renal transplant rejection. We show that Met-RANTES, a chemokine receptor antagonist, suppresses recruitment of inflammatory cells into renal allografts. In a renal transplant model (Fisher RT1lvl rat kidney into Lewis RT1l rat) where no additional immune suppressant was used, Met-RANTES-treated animals showed a significant reduction in vascular injury score (16.10 ± 5.20 vs. 62.67 ± 18.64) and tubular damage score (15.70 ± 5.22 vs. 33.00 ± 6.44) relative to untreated animals. In a more severe rejection model (Brown-Norway RT1n rat kidney into Lewis RT11 rat), Met-RANTES significantly augmented low-dose cyclosporin A treatment to reduce all aspects of renal injury including interstitial inflammation (score 71.00 ± 6.10 vs. 157.30 ± 21.30). The majority of infiltrating cells in these models (60–70%) consisted of monocytes. Potential mechanisms of action of Met-RANTES were tested using monocyte attachment assays on microvascular endothelium under physiological flow conditions. Preexposure of microvascular endothelium to RANTES resulted in RANTES immobilization and RANTES-induced firm adhesion of monocytes only after prestimulation of the endothelium with IL-1ß. Met-RANTES completely inhibited this RANTES-mediated arrest. Thus, Met-RANTES may counter acute rejection by blocking leukocyte firm adhesion to inflamed endothelium.—Gröne, H.-J., Weber, C., Weber, K. S. C., Gröne, E. F., Rabelink, T., Klier, C. M., Wells, T. N. C., Proudfoot, A. E., Schlöndorff, D., Nelson, P. J. Met-RANTES reduces vascular and tubular damage during acute renal transplant rejection: blocking monocyte arrest and recruitment.
Key Words: chemokine receptors • inflammation • monocyte • endothelium
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R. Horuk, C. Clayberger, A. M. Krensky, Z. Wang, H.-J. Grone, C. Weber, K. S. C. Weber, P. J. Nelson, K. May, M. Rosser, et al. A Non-peptide Functional Antagonist of the CCR1 Chemokine Receptor Is Effective in Rat Heart Transplant Rejection J. Biol. Chem., February 2, 2001; 276(6): 4199 - 4204. [Abstract] [Full Text] [PDF]
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M. Wong, S. Uddin, B. Majchrzak, T. Huynh, A. E. I. Proudfoot, L. C. Platanias, and E. N. Fish RANTES Activates Jak2 and Jak3 to Regulate Engagement of Multiple Signaling Pathways in T Cells J. Biol. Chem., March 30, 2001; 276(14): 11427 - 11431. [Abstract] [Full Text] [PDF]
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