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Selective Inhibition of CCR2 Expressing Lymphomyeloid Cells in Experimental Autoimmune Encephalomyelitis by a GM-CSF-MCP1 Fusokine¹

Moutih Rafei^*, Philippe M. Campeau^*, Jian Hui Wu^*,, Elena Birman^*, Kathy Forner^*, Marie-Noelle Boivin^* and Jacques Galipeau^2,*,

^* The Montreal Center for Experimental Therapeutics in Cancer, Department of Oncology, McGill University, Division of Hematology/Oncology, Jewish General Hospital, McGill University, Montreal, Canada

We describe the generation of a fusion cytokine consisting of GM-CSF in tandem with N-terminal-truncated MCP-1 (6-76), hereafter GMME1. Treatment of activated T cells with recombinant GMME1 protein leads to proinflammatory cytokine reduction and apoptosis via a CCR2-restricted pathway. Similarly, cell death is triggered in macrophages cultured with GMME1, while an inhibition of Ab production from plasma cells is observed. Treatment of CD4 T cells derived from experimental autoimmune encephalomyelitis mice with GMME1 leads to p38 hyperphosphorylation, inhibition of p44/42, AKT and STAT3 phosphorylation, and caspase-3 activation. GMME1 administration to experimental autoimmune encephalomyelitis mice suppresses symptomatic disease and correlates with decreased levels of inflammatory cytokines including IL-17, MOG-specific Ab titers, and blockade of CD4 and CD8 T cell infiltration in spinal cords. We propose that GMME1 defines a new class of agents for the treatment of autoimmune ailments by selectively targeting lymphomyeloid cells expressing CCR2.

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 Canadian Institute of Health Research Grant CIHR MOP-15017 (to J.G.). Moutih Rafei is a recipient of a Fonds de Recherches en Santé du Québec (FRSQ).

² Address correspondence and reprint requests to Dr. Jacques Galipeau, Montreal Center for Experimental Therapeutics in Cancer, McGill University, 3755 Cote Ste-Catherine Road, Montreal, Canada. E-mail address: jacques.galipeau{at}mcgill.ca

³ Abbreviations used in this paper: GPCR, G protein-coupled receptor; mpCCL2, MMP-processed CCL2; EAE, experimental autoimmune encephalomyelitis; MS, multiple sclerosis; qRT-PCR, quantitative RT-PCR; WT, wild type; MSC, mesenchymal stromal cell; PI, propidium iodine.

⁴ The online version of this article contains supplemental material.

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The JI 2009 182: 2555-2556. [Full Text]