A Novel Synthetic GMCSF and MCP3 Fusion Cytokine Induces IL10-Producing B Cells with Immune Modulatory Properties on Antigen Presentation and Th17 Development

Abstract 587

Therapeutic strategies based on the modulation of immune system can be exploited to treat a variety of pathologies including autoimmune diseases and cancer. We previously described the immune suppressive and receptor-specific apoptotic effect of a fusion cytokine GMME1, generated by the linkage of granulocyte macrophage-colony stimulating factor (GM-CSF) at the N-terminal of MCP1 (6-76). To better understand the immunobiology of N-terminal-modified CC chemokine, we described the novel function of GMCSF-MCP3 (5-76) (GMME3) in its induction of IL10+, regulatory-competent B cells. Ex vivo cultured B lymphocyte with GMME3 leads to a significant increase in S and G2/M phases, IL10 production and the expression of CD1.d and CD5. Treatment of experimental autoimmune encephalomyelitis (EAE) mice with GMME3-activated wild type B cells (B_GMME3), but not IL10 null B cells, significantly inhibits the disease progression and immune infiltrates into the CNS. We demonstrated that the mechanism by which B_GMME3 exerts their effect is through IL10-mediated inhibition of class II antigen presentation of macrophages; moreover, B_GMME3 inhibits the reactivation of EAE-derived Th17 cells by augmenting Th1 pathway. Hence, N-terminal-GMCSF-fused CC chemokine, GMME3 modulates the immunological phenotype of B cells in a manner permissive for personalized cell therapy of autoimmune ailments.