A non-peptide functional antagonist of the CCR1 chemokine receptor is effective in rat heart transplant rejection.
Chemokines like RANTES appear to play a role in organ transplant rejection. Because RANTES is a potent agonist for the chemokine receptor CCR1, we examined whether the CCR1 receptor antagonist BX471 is efficacious in a rat heterotopic heart transplant rejection model. Treatment of animals with BX471 and a subtherapeutic dose of cyclosporin (2.5 mg/kg), which is by itself ineffective in prolonging transplant rejection, is much more efficacious in prolonging transplantation rejection than animals treated with either cyclosporin or BX471 alone. We have examined the mechanism of action of the CCR1 antagonist in in vitro flow assays over microvascular endothelium and have discovered that the antagonist blocks the firm adhesion of monocytes triggered by RANTES on inflamed endothelium. Together, these data demonstrate a significant role for CCR1 in allograft rejection.
Horuk
R
R
Departments of Immunology and Discovery Research, Berlex Biosciences, Richmond, California 94806, USA.
Clayberger
C
C
Krensky
A M
AM
Wang
Z
Z
Grone
H J
HJ
Weber
C
C
Weber
K S
KS
Nelson
P J
PJ
May
K
K
Rosser
M
M
Dunning
L
L
Liang
M
M
Buckman
B
B
Ghannam
A
A
Ng
H P
HP
Islam
I
I
Bauman
J G
JG
Wei
G P
GP
Monahan
S
S
Xu
W
W
Snider
R M
RM
Morrissey
M M
MM
Hesselgesser
J
J
Perez
H D
HD
D000818:Animals; D002460:Cell Line; D016572:Cyclosporine / Q000008:administration & dosage; D006084:Graft Rejection; D006085:Graft Survival; D016027:Heart Transplantation; D006801:Humans; D008297:Male; D010671:Phenylurea Compounds / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D054389:Receptors, CCR1; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors* / Q000502:physiology
C515300:CCR1 protein, human; C515302:Ccr1 protein, rat; D010671:Phenylurea Compounds; D010880:Piperidines; D054389:Receptors, CCR1; D019707:Receptors, Chemokine; D016572:Cyclosporine; C411885:BX 471