Met-RANTES reduces vascular and tubular damage during acute renal transplant rejection: blocking monocyte arrest and recruitment.
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.
Gröne
H J
HJ
German Cancer Research Center, Department of Experimental Pathology, Germany.
Weber
C
C
Weber
K S
KS
Gröne
E F
EF
Rabelink
T
T
Klier
C M
CM
Wells
T N
TN
Proudfood
A E
AE
Schlöndorff
D
D
Nelson
P J
PJ
D000818:Animals; D018946:Chemokine CCL5 / Q000031:analogs & derivatives* / Q000276:immunology; D016572:Cyclosporine / Q000008:administration & dosage; D004730:Endothelium, Vascular / Q000276:immunology / Q000473:pathology; D006084:Graft Rejection / Q000276:immunology* / Q000517:prevention & control; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D016030:Kidney Transplantation; D007684:Kidney Tubules / Q000276:immunology / Q000473:pathology; D008297:Male; D009000:Monocytes / Q000276:immunology* / Q000473:pathology; D051381:Rats; D011914:Rats, Inbred BN; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D014181:Transplantation Immunology; D014184:Transplantation, Homologous
D018946:Chemokine CCL5; D007166:Immunosuppressive Agents; C108335:RANTES, Met-; D016572:Cyclosporine