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

FASEB J. 1999 Aug;13(11):1371-83.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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

Substances

  • Chemokine CCL5
  • Immunosuppressive Agents
  • RANTES, Met-
  • Cyclosporine