Selective inhibition of CCR2 expressing lymphomyeloid cells in experimental autoimmune encephalomyelitis by a GM-CSF-MCP1 fusokine

J Immunol. 2009 Mar 1;182(5):2620-7. doi: 10.4049/jimmunol.0803495.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Apoptosis / genetics
  • Apoptosis / immunology
  • Cells, Cultured
  • Chemokine CCL2 / administration & dosage
  • Chemokine CCL2 / genetics*
  • Chemokine CCL2 / therapeutic use
  • Coculture Techniques
  • Encephalomyelitis, Autoimmune, Experimental / immunology*
  • Encephalomyelitis, Autoimmune, Experimental / pathology
  • Encephalomyelitis, Autoimmune, Experimental / therapy
  • Female
  • Granulocyte-Macrophage Colony-Stimulating Factor / administration & dosage
  • Granulocyte-Macrophage Colony-Stimulating Factor / genetics*
  • Granulocyte-Macrophage Colony-Stimulating Factor / therapeutic use
  • HeLa Cells
  • Humans
  • Lymphocytes / immunology*
  • Lymphocytes / metabolism
  • Lymphocytes / pathology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Molecular Sequence Data
  • Myeloid Cells / immunology*
  • Myeloid Cells / metabolism
  • Myeloid Cells / pathology
  • Receptors, CCR2 / antagonists & inhibitors*
  • Receptors, CCR2 / biosynthesis
  • Receptors, CCR2 / deficiency
  • Receptors, CCR2 / genetics*
  • Recombinant Fusion Proteins / administration & dosage
  • Recombinant Fusion Proteins / chemical synthesis
  • Recombinant Fusion Proteins / physiology*

Substances

  • Ccl2 protein, mouse
  • Ccr2 protein, mouse
  • Chemokine CCL2
  • Receptors, CCR2
  • Recombinant Fusion Proteins
  • Granulocyte-Macrophage Colony-Stimulating Factor