[Reduction of acute kidney transplantation rejection by the chemokine receptor antagonist Met-RANTES].
Chemokines contribute to the mononuclear cell infiltrate in vessels and interstitium which is characteristic of renal transplant rejection. By employing the chemokine receptor blocker Met-RANTES it was shown that recruitment of inflammatory cells into renal allografts could be significantly suppressed. In a renal transplant model (Fisher RT1(1v1) rat kidney into Lewis RT1(1) rat) 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 severe rejection model (Brown-Norway RT1n 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). In a monocyte attachment assay on microvascular endothelium under physiological flow conditions exposure of microvascular endothelium to RANTES resulted in RANTES immobilization and RANTES-induced firm adhesion of monocytes only after prestimulation of the endothelium with IL-1 beta. Met-RANTES completely inhibited this RANTES-mediated arrest. Thus, Met-RANTES can reduce acute rejection by impeding leukocyte arrest to inflamed endothelium.
Gröne
H J
HJ
Deutsches Krebsforschungszentrum, Abteilung für Zelluläre und Molekulare Pathologie, Heidelberg.
Weber
C
C
Weber
K S
KS
Gröne
E F
EF
Klier
C M
CM
Wells
T N
TN
Proudfoot
A E
AE
Schlöndorff
D
D
Nelson
P J
PJ
D000208:Acute Disease; D000818:Animals; D018946:Chemokine CCL5 / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006084:Graft Rejection / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D016030:Kidney Transplantation / Q000276:immunology* / Q000473:pathology; D008297:Male; D051381:Rats; D011914:Rats, Inbred BN; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors*; D014184:Transplantation, Homologous
D018946:Chemokine CCL5; C108335:RANTES, Met-; D019707:Receptors, Chemokine