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Membrane-Bound CC Chemokine Inhibitor 35K Provides Localized Inhibition of CC Chemokine Activity In Vitro and In Vivo¹

Christina A. Bursill^*,, Jenna L. Cash, Keith M. Channon^* and David R. Greaves^2,

^* Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom; and Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom

CC chemokines mediate mononuclear cell recruitment and activation in chronic inflammation. We have shown previously that gene transfer using recombinant adenoviruses, encoding a soluble CC chemokine-binding protein of vaccinia virus 35K, can dramatically reduce atherosclerosis and vein graft remodeling in apolipoprotein E knockout mice. In this study, we report the development of a membrane-bound form of 35K (m35K), tagged with GFP, which allows for localized, broad-spectrum CC chemokine blockade. In vitro experiments indicate that m35K-expressing cells no longer undergo CC chemokine-induced chemotaxis, and m35K-expressing cells can locally deplete the CC chemokines RANTES (CCL5) and MIP-1 (CCL3) from supernatant medium. This sequestration of CC chemokines can prevent chemotaxis of bystander cells to CC, but not CX₃C chemokines. Intraperitoneal injection of mice with an adenovirus-encoding m35K leads to a significant (44%) decrease in leukocyte recruitment into the peritoneal cavity in a sterile peritonitis model. Intravenous adenovirus-encoding m35K delivery leads to m35K expression in hepatocytes, which confers significant protection against liver damage (75% reduction in liver enzymes) in a Con A-induced hepatitis model. In summary, we have generated a membrane-bound CC chemokine-binding protein (m35K) that provides localized broad-spectrum CC chemokine inhibition in vitro and in vivo. m35K may be a useful tool to study the role of CC chemokines in leukocyte trafficking and block the recruitment of monocytes in chronic inflammation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the British Heart Foundation.

² Address correspondence and reprint requests to Dr. David R. Greaves, Sir William Dunn School of Pathology, South Parks Road, Oxford OX1 3RE, U.K. E-mail address: david.greaves{at}path.ox.ac.uk

³ Abbreviations used in this paper: Ad, adenoviral; Ad35K, Ad-encoding soluble 35K; Adm35K, adenovirus-encoding m35K; ALT, alanine aminotransferase; AST, aspartate aminotransferase; FasL, Fas ligand; HA, hemagglutinin; ApoE, apolipoprotein E; KO, knockout; m35K, membrane-bound 35K; vp, viral particle.

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