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Targeted replacement of rodent CCR2 with the human orthologue CCR2B: A mouse model for in vivo analysis of human target‐selective small molecule MCP‐1 receptor antagonists
Author(s) -
Prosser Haydn M.,
Cooper David G.,
Forbes Ian T.,
Geppert Martin,
Gribble Andrew D.,
Grau Evelyn V.,
Groot Pieter H.,
Harper Alex J.,
Moores Kitty E.,
Pickering Susan J.,
Piercy Valerie
Publication year - 2002
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/ddr.10044
Subject(s) - ccr2 , in vivo , biology , cell culture , microbiology and biotechnology , rodent , gene targeting , in vitro , mutant , receptor , gene , chemokine , chemokine receptor , genetics , ecology
Abstract Rodent models for testing the efficacy of lead compounds are often invalidated by species selectivity of the compounds. The advent of mouse embryonic stem cell technology has allowed the development of genetically engineered mouse strains that incorporate a specific human gene in place of the orthologous mouse gene, a so‐called knock‐in mouse. This study describes the generation and validation of a mutant mouse line that expresses human CCR2B as a functional substitute for murine CCR2. The human CCR2B knock‐in mice are viable and appear normal. In vitro assays indicate that the CCR2B knock‐in is functionally expressed, giving a macrophage chemotactic profile in response to JE or MCP‐1 that is similar to human peripheral blood monocytes rather than that of a murine macrophage cell line. In addition, the human selective CCR2B antagonist, SB‐399721, was a more potent inhibitor of CCR2B knock‐in macrophages in response to hMCP‐1 than JE. The ability of the human CCR2B gene to functionally substitute for the mouse orthologue in vivo is demonstrated by a normal inflammatory response to intraperitoneal thioglycollate injection. Drug Dev. Res. 55:197–209, 2002. © 2002 Wiley‐Liss, Inc.