RT Journal Article
SR Electronic
T1 LATE-BREAKING ABSTRACT: A novel role for CCR3 in promoting airways hyperreactivity; Role for CCR3-muscarinic M3 receptor heterodimers
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP OA288
DO 10.1183/13993003.congress-2015.OA288
VO 46
IS suppl 59
A1 Kevin Bacon
A1 Emma Moss
A1 Karen Bingham
A1 Louis-Philippe Boulet
A1 Mark Fitzgerald
A1 Gail Gauvreau
A1 Paul O'Byrne
A1 Taylor Gilliland
A1 Tracy Handel
A1 Tai-Wei Ly
A1 Stefen Boehme
YR 2015
UL http://erj.ersjournals.com/content/46/suppl_59/OA288.abstract
AB We have developed a novel therapeutic inhibitor against the chemokine receptor CCR3 for allergic asthma that significantly inhibited the MCh PC20 response in a Phase IIa trial in mild-to-moderate asthmatics. In vivo, AXP1275 had shown significant efficacy in reducing inflammatory mediators and cellular infiltrates in non-human primate models of allergic asthma, and, surprisingly, had also inhibited airways hyperreactivity and methacholine constriction responses (PC150). In addition, inhibition was seen with ex-vivo carbachol (CCh)-induced constriction in human lung tissue. In order to discern pharmacologically-relevant mechanisms for inhibition of CCh-induced lung constriction by AXP1275, we have investigated the receptor pharmacology of CCR3 in human lung tissue. Immunohistochemically, CCR3 is present on epithelium and smooth muscle, and is co-localized with the muscarinic M3 receptor. In receptor transfectants, CCL11 and CCh cross-sensitize agonist-induced calcium mobilization, suggesting cooperativity between CCR3 and M3. AXP1275 and muscarinic receptor antagonists inhibit responses in a similarly-cooperative manner. Bioluminescence resonance energy transfer (BRET) assays demonstrated that CCR3 and M3 heterodimerize, and this was further supported by receptor co-immunoprecipitation assays. Receptor heterodimerization of CCR3 and M3 on non-leukocytic cells in vivo may provide a plausible explanation for the efficacy of CCR3-selective inhibitors on the hyperreactivity response in asthma.