Selective Inhibition of CCR2 Expressing Lymphomyeloid Cells in Experimental Autoimmune Encephalomyelitis by a GM-CSF-MCP1 Fusokine
Moutih Rafei, Philippe M. Campeau, Jian Hui Wu,, Elena Birman, Kathy Forner, Marie-Noelle Boivin and Jacques Galipeau
The Journal of Immunology, 2009, 182, 2620 -2627 doi:10.4049/jimmunol.0803495
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.
