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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 TGF?/IL6 differentiated Th17 cells by altering their polarization toward a Th1 or Th2 phenotype. The secretion of interferon-? (IFN?) 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.

SUBMITTER: Hsieh J 

PROVIDER: S-EPMC3437591 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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Inducible IL10(+) suppressor B cells inhibit CNS inflammation and T helper 17 polarization.

Hsieh Jeremy J   Williams Patrick P   Rafei Moutih M   Birman Elena E   Cuerquis Jessica J   Yuan Shala S   Wu JianHui J   Galipeau Jacques J  

Molecular therapy : the journal of the American Society of Gene Therapy 20120703 9


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  ...[more]

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