R. Horuk et al., A non-peptide functional antagonist of the CCR1 chemokine receptor is effective in rat heart transplant rejection, J BIOL CHEM, 276(6), 2001, pp. 4199-4204
Chemokines like RANTES appear to play a role in organ transplant rejection.
Because RANTES is a potent agonist for the chemokine receptor CCR1, we exa
mined whether the CCR1 receptor antagonist BX471 is efficacious in a rat he
terotopic heart transplant rejection model. Treatment of animals with BX471
and a subtherapeutic dose of cyclosporin (2.5 mg/kg), which is by itself i
neffective in prolonging transplant rejection, is much more efficacious in
prolonging transplantation rejection than animals treated with either cyclo
sporin 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 trigg
ered by RANTES on inflamed endothelium. Together, these data demonstrate a
significant role for CCR1 in allograft rejection.