Met-RANTES reduces vascular and tubular damage during acute renal transplant rejection: blocking monocyte arrest and recruitment

• Published in: The FASEB journal Vol. 13; no. 11; p. 1371
• Main Authors: Gröne, H J, Weber, C, Weber, K S, Gröne, E F, Rabelink, T, Klier, C M, Wells, T N, Proudfood, A E, Schlöndorff, D, Nelson, P J
• Format: Journal Article
• Language: English
• Published: United States 01.08.1999
• Subjects: Animals; Chemokine CCL5 - analogs & derivatives; Chemokine CCL5 - immunology; Cyclosporine - administration & dosage; Endothelium, Vascular - immunology; Endothelium, Vascular - pathology; Graft Rejection - immunology; Graft Rejection - prevention & control; Humans; Immunosuppressive Agents - administration & dosage; Kidney Transplantation; Kidney Tubules - immunology; Kidney Tubules - pathology; Male; Monocytes - immunology; Monocytes - pathology; Rats; Rats, Inbred BN; Rats, Inbred F344; Rats, Inbred Lew; Transplantation Immunology; Transplantation, Homologous
• ISSN: 0892-6638
• DOI: 10.1096/fasebj.13.11.1371

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 RT1(lvl) rat kidney into Lewis RT1(l) 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 RT1(n) rat kidney into Lewis RT1(1) 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-1beta. Met-RANTES completely inhibited this RANTES-mediated arrest. Thus, Met-RANTES may counter acute rejection by blocking leukocyte firm adhesion to inflamed endothelium.