Engagement of two distinct binding domains on CCL17 is required for signaling through CCR4 and establishment of localized inflammatory conditions in the lung

PloS One
Sandra Santulli-MarottoMary Ryan

Abstract

CCL17 (TARC) function can be completely abolished by mAbs that block either one of two distinct sites required for CCR4 signaling. This chemokine is elevated in sera of asthma patients and is responsible for establishing inflammatory sites through CCR4-mediated recruitment of immune cells. CCL17 shares the GPCR CCR4, with CCL22 (MDC) but these two chemokines differentially affect the immune response. To better understand chemokine mediated effects through CCR4, we have generated chimeric anti-mouse CCL17 surrogate antibodies that inhibit function of this ligand in vitro and in vivo. The affinities of the surrogate antibodies for CCL17 range from 685 pM for B225 to 4.9 nM for B202. One antibody, B202, also exhibits weak binding to CCL22 (KD∼2 µM) and no binding to CCL22 is detectable with the second antibody, B225. In vitro, both antibodies inhibit CCL17-mediated calcium mobilization, β-arrestin recruitment and chemotaxis; B202 can also partially inhibit CCL22-mediated β-arrestin recruitment. Both B202 and B225 antibodies neutralize CCL17 in vivo as demonstrated by reduction of methacholine-induced airway hyperreactivity in the A. fumigatus model of asthma. That both antibodies block CCL17 function but only B202 shows any inhibi...Continue Reading

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Citations

Dec 20, 2015·Monoclonal Antibodies in Immunodiagnosis and Immunotherapy·Sandra Santulli-MarottoMary Ryan
Oct 8, 2015·Scientific Reports·Dayana AbboudNelly Frossard
Dec 14, 2016·Drug Discovery Today·Dayana Abboud, Julien Hanson
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Dec 25, 2015·Journal of Leukocyte Biology·Caroline A AndersonJames E Pease

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Methods Mentioned

BETA
ELISA
biosensor
chip
Assay
equilibrium affinity assay
competition binding

Software Mentioned

GraphPad Prizm
Scrubber
GraphPad Prism
BioLogic
Biacore

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