J. Exp. Med., Volume 188, Number 1, July 1, 1998 193-198

In Vivo Inhibition of CC and CX₃C Chemokine-induced Leukocyte Infiltration and Attenuation of Glomerulonephritis in Wistar-Kyoto (WKY) Rats by vMIP-II

By Shizhong Chen,^* Kevin B. Bacon, Li Li,^* Gabriela E. Garcia,^* Yiyang Xia,^* David Lo,^* Darren A. Thompson,^§ Michael A. Siani,^§ Tadashi Yamamoto, Jeffrey K. Harrison,^¶ and Lili Feng^*

From the ^* Department of Immunology, The Scripps Research Institute, La Jolla, California 92037;  Neurocrine Biosciences, San Diego, California 92121; ^§ Gryphon Sciences, South San Francisco, California 94908; the  Department of Pathology, Instutute of Nephrology, Niigata University School of Medicine, Niigata 951, Japan; and the ^¶ Department of Pharmacology and Therapeutics, University of Florida, Gainesville, Florida 32610

Chemokines play a central role in immune and inflammatory responses. It has been observed recently that certain viruses have evolved molecular piracy and mimicry mechanisms by encoding and synthesizing proteins that interfere with the normal host defense response. One such viral protein, vMIP-II, encoded by human herpesvirus 8, has been identified with in vitro antagonistic activities against CC and CXC chemokine receptors. We report here that vMIP-II has additional antagonistic activity against CX₃CR1, the receptor for fractalkine. To investigate the potential therapeutic effect of this broad-spectrum chemokine antagonist, we studied the antiinflammatory activity of vMIP-II in a rat model of experimental glomerulonephritis induced by an antiglomerular basement membrane antibody. vMIP-II potently inhibited monocyte chemoattractant protein 1-, macrophage inflammatory protein 1-, RANTES (regulated on activation, normal T cell expressed and secreted)-, and fractalkine-induced chemotaxis of activated leukocytes isolated from nephritic glomeruli, significantly reduced leukocyte infiltration to the glomeruli, and markedly attenuated proteinuria. These results suggest that molecules encoded by some viruses may serve as useful templates for the development of antiinflammatory compounds.

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