title: Inducible IL10(+) suppressor B cells inhibit CNS inflammation and T helper 17 polarization.
abstract: Granulocyte-macrophage colony-stimulating factor (GMCSF) and MCP3 (aka CCL7) exert complementary, nonoverlapping, proimmune effects on responsive lymphoid and myeloid cells. We hypothesized that a synthetic cytokine linking GMCSF to MCP3 (hereafter GMME3) as part of a single polypeptide would acquire novel, therapeutically desirable immunomodulatory properties. We demonstrate that GMME3 has enhanced CC-chemokine receptor (CCR)-mediated intracellular Ca(++) mobilization with selective effects on the CD21(hi)CD24(hi) CD1.d(hi) subset of splenic B cells inducing substantial interleukin 10 (IL10) production. We demonstrate that B(GMME3) exert their suppressive effect through an IL10-mediated inhibition of antigen presentation. More importantly, B(GMME3) inhibit the reactivation of encephalomyelitis (EAE)-derived or TGFβ/IL6 differentiated Th17 cells by altering their polarization toward a Th1 or Th2 phenotype. The secretion of interferon-γ (IFNγ) and IL4 in turn inhibits IL17 production. The adoptive transfer of B(GMME3), but not IL10(-/-) B(GMME3) cells, to mice symptomatic with experimental autoimmune encephalitis significantly improves their disease score and inhibits lymphoid infiltration into the central nervous system (CNS). We propose that designed CCR modulators such as GMME3, allows for conversion of naive B-cells to a novel suppressor phenotype allowing for the personalized cell therapy of autoimmune ailments.
authors: The Montreal Center for Experimental Therapeutics in Cancer, Lady Davis Institute, McGill University, Montreal, Quebec, Canada; Department of Hematology and Oncology and Pediatrics, Emory University Winship Cancer Institute, Atlanta, Georgia, USA.
authors: Jeremy
authors: J
authors: Hsieh
authors: The Montreal Center for Experimental Therapeutics in Cancer, Lady Davis Institute, McGill University, Montreal, Quebec, Canada.
authors: Patrick
authors: P
authors: Williams
authors: Institute for Research in Immunology and Cancer, University de Montreal, Montreal, Quebec, Canada.
authors: Moutih
authors: M
authors: Rafei
authors: The Montreal Center for Experimental Therapeutics in Cancer, Lady Davis Institute, McGill University, Montreal, Quebec, Canada.
authors: Elena
authors: E
authors: Birman
authors: The Montreal Center for Experimental Therapeutics in Cancer, Lady Davis Institute, McGill University, Montreal, Quebec, Canada.
authors: Jessica
authors: J
authors: Cuerquis
authors: The Montreal Center for Experimental Therapeutics in Cancer, Lady Davis Institute, McGill University, Montreal, Quebec, Canada; Department of Hematology and Oncology and Pediatrics, Emory University Winship Cancer Institute, Atlanta, Georgia, USA.
authors: Shala
authors: S
authors: Yuan
authors: The Montreal Center for Experimental Therapeutics in Cancer, Lady Davis Institute, McGill University, Montreal, Quebec, Canada.
authors: JianHui
authors: J
authors: Wu
authors: The Montreal Center for Experimental Therapeutics in Cancer, Lady Davis Institute, McGill University, Montreal, Quebec, Canada; Department of Hematology and Oncology and Pediatrics, Emory University Winship Cancer Institute, Atlanta, Georgia, USA. Electronic address: Jgalipe@emory.edu.
authors: Jacques
authors: J
authors: Galipeau
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D017951:Antigen Presentation; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002118:Calcium / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation; D002490:Central Nervous System / Q000276:immunology / Q000473:pathology; D054410:Chemokine CCL7 / Q000235:genetics / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000276:immunology; D057809:HEK293 Cells; D006801:Humans; D056747:Immunomodulation; D007167:Immunotherapy; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D016753:Interleukin-10 / Q000096:biosynthesis / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D013154:Spleen / Q000276:immunology / Q000473:pathology; D058504:Th17 Cells / Q000276:immunology* / Q000378:metabolism
chemical_list: C515450:CCL7 protein, human; D054410:Chemokine CCL7; D011993:Recombinant Fusion Proteins; D016753:Interleukin-10; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D002118:Calcium