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A new evidence of therapeutic effects of Mycobacterium bovis BCG vaccine to experimental autoimmune encephalomyelitis (EAE): BCG-mediated suppression of Th17 response in EAE mice induced using an adjuvant without mycobacterial antigen.
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  • Goro Matsuzaki,
  • Naoko Teruya,
  • Hideyasu Kiyohara,
  • Keiko Arai,
  • Yukihiro Shibuya,
  • Yasushi Chuma,
  • Kazuhiro Matsuo
Goro Matsuzaki
University of the Ryukyus
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Naoko Teruya
University of the Ryukyus
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Hideyasu Kiyohara
Japan BCG Laboratory Kiyose Research Center
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Keiko Arai
Japan BCG Laboratory Kiyose Research Center
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Yukihiro Shibuya
Japan BCG Laboratory Kiyose Research Center
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Yasushi Chuma
Japan BCG Laboratory Kiyose Research Center
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Kazuhiro Matsuo
Japan BCG Laboratory Kiyose Research Center
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Abstract

Multiple sclerosis (MS) is an autoimmune disease mediated by myelin autoantigen-specific T cells. Experimental autoimmune encephalomyelitis (EAE) induced by immunization of mice with a myelin oligodendrocyte glycoprotein (MOG) peptide emulsified in killed Mycobacterium tuberculosis-containing complete Freund’s adjuvant (CFA-EAE) is frequently used as a model of MS. Mycobacterium bovis BCG, a vaccine strain with various biological response modifier activity, has been reported to ameliorate clinical symptoms of the CFA-EAE although precise mechanism has not yet been documented. Since the CFA-EAE uses adjuvant with mycobacterial antigens, it is possible that mycobacterial antigen-specific T cells induced by CFA and those by therapeutic BCG inoculation recognize same antigens, and the cross-reactivity modulate the EAE. To exclude the influence of the cross-reactivity, we established a modified murine EAE model (CWS-EAE) which does not induce mycobacterial antigen-specific T cells. Inoculation of BCG 6 days after the CWS-EAE induction successfully ameliorated EAE symptoms, suggesting the therapeutic effects of BCG is independent of the mycobacterial antigen-specific T cells induced by CFA-EAE protocol. With the CWS-EAE model, we confirmed that induction of MOG-specific Th17 in the spleen and central nervous system (CNS) decreased with disappearance of demyelination lesions by the BCG inoculation. The amelioration of CNS pathology was not linked to changes in the number of macrophages, neutrophil and conventional dendritic cells (DC) but associated with decrease of plasmacytoid DC in CNS. The results suggest that BCG inoculation suppress both systemic and CNS Th17 response in the EAE mice and the mechanism may involve modulation of plasmacytoid DC.