A Non-peptide Functional Antagonist of the CCR1 Chemokine Receptor Is Effective in Rat Heart Transplant Rejection

Department of Cardiothoracic Surgery, Stanford University, Palo Alto, California, United States
Journal of Biological Chemistry (Impact Factor: 4.57). 03/2001; 276(6):4199-204. DOI: 10.1074/jbc.M007457200
Source: PubMed


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.

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    • "Table 2 List of chemokine receptors antagonists Receptor Antagonist References CCR1 CCL26 Petkovic et al. (2004) bx471 Horuk et al. (2001) "
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    • "During acute rejection, recipient T cell activation fuelled by graft co-stimulatory molecules such as CD40/CD154 up-regulates expression of IFN-γ [6, 32], interleukins 1, 6, 8 and 12 as well as TNF-α and MIP-1α in dendritic cells [3] and that of E-selectin, VCAM-1 and ICAM-1 in the endothelial cells of the graft blood vessels [16]. Furthermore, MCP-1/CCL2 and RANTES/CCL5, potent chemotactic factors for monocytes, CD4+ and CD8+ positive T cells, basophils, and eosinophils [26] have been shown, albeit with different kinetics, to be up-regulated in cardiac allografts [9, 13, 27], an effect that may also have important consequences for chronic graft rejection, i.e. transplant arteriosclerosis [33]. As a result, recruitment and invasion of mononuclear cells, namely monocytes and T cells, into the transplant is augmented with the ensuing acute inflammatory response presumably leading to graft loss. "
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