Abstract
Monocyte chemoattractant protein-1 (MCP-1, CCL-2) binds to the Duffy antigen (DARC) on red blood cells, which act as a sink for several chemokines including MCP-1. In this study it is hypothesized that DARC may alter the pharmacokinetics of infused recombinant human MCP-1 (rhMCP-1). The primary aim of this first in man trial is to compare the pharmacokinetics of rhMCP-1 in Duffy positive and negative individuals. A randomized, double-blinded, placebo-controlled dose escalation trial was conducted on 36 healthy volunteers. Subjects received infusions of 0.02-2.0 microg/kg rhMCP-1 or placebo for one hour. RhMCP-1 displayed linear pharmacokinetics. Duffy negative individuals reached maximal plasma levels significantly earlier, but overall plasma concentration profiles were not altered. rhMCP-1 markedly increased monocyte counts, and estimated EC50 values were 10-fold higher in Duffy positive than in Duffy negative subjects. Increased monocyte counts were associated with decreased surface expression of intercellular adhesion molecule 1 (ICAM-1, CD54). In contrast, neither CCR-2 or CD11b expression, nor markers of platelet or endothelial activation, inflammation and coagulation were altered. RhMCP-1 is a highly selective chemoattractant for monocytes in humans. The Duffy antigen only minimally alters the pharmacokinetics of rhMCP-1 for doses up to 2 microg/kg.
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