Immunomodulatory Cell Therapy Using αGalCer-Pulsed Dendritic Cells Ameliorates Heart Failure in a Murine Dilated Cardiomyopathy Model

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  • Ikeda, Masataka
    Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University Division of Cardiovascular Medicine, Research Institute of Angiocardiology, Faculty of Medical Sciences, Kyushu University Department of Immunoregulatory Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University
  • Ide, Tomomi
    Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University Division of Cardiovascular Medicine, Research Institute of Angiocardiology, Faculty of Medical Sciences, Kyushu University Department of Immunoregulatory Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University
  • Matsushima, Shouji
    Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University Division of Cardiovascular Medicine, Research Institute of Angiocardiology, Faculty of Medical Sciences, Kyushu University
  • Ikeda, Soichiro
    Division of Cardiovascular Medicine, Research Institute of Angiocardiology, Faculty of Medical Sciences, Kyushu University
  • Okabe, Kosuke
    Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University Division of Cardiovascular Medicine, Research Institute of Angiocardiology, Faculty of Medical Sciences, Kyushu University
  • Ishikita, Akihito
    Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University Division of Cardiovascular Medicine, Research Institute of Angiocardiology, Faculty of Medical Sciences, Kyushu University
  • Tadokoro, Tomonori
    Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University Division of Cardiovascular Medicine, Research Institute of Angiocardiology, Faculty of Medical Sciences, Kyushu University
  • Sada, Masashi
    Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University Division of Cardiovascular Medicine, Research Institute of Angiocardiology, Faculty of Medical Sciences, Kyushu University
  • Abe, Ko
    Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University Division of Cardiovascular Medicine, Research Institute of Angiocardiology, Faculty of Medical Sciences, Kyushu University
  • Sato, Midori
    Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University Division of Cardiovascular Medicine, Research Institute of Angiocardiology, Faculty of Medical Sciences, Kyushu University
  • Hanada, Akiko
    Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University Division of Cardiovascular Medicine, Research Institute of Angiocardiology, Faculty of Medical Sciences, Kyushu University
  • Arai, Shinobu
    Department of Early Childhood and Elementary Education, Faculty of Education, Nakamura Gakuen University
  • Ohtani, Kisho
    Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University Division of Cardiovascular Medicine, Research Institute of Angiocardiology, Faculty of Medical Sciences, Kyushu University
  • Nonami, Atsushi
    Center for Advanced Medical Innovation, Kyushu University Hospital
  • Mizuno, Shinichi
    Department of Health Sciences (S. Mizuno), Faculty of Medical Sciences, Kyushu University
  • Morimoto, Sachio
    Department of Health Sciences at Fukuoka, International University of Health and Welfare
  • Motohashi, Shinichiro
    Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University Department of Medical Immunology, Graduate School of Medicine, Chiba University
  • Akashi, Koichi
    Department of Medicine and Biosystemic Science (K. Akashi), Faculty of Medical Sciences, Kyushu University
  • Taniguchi, Masaru
    Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences
  • Tsutsui, Hiroyuki
    Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University Division of Cardiovascular Medicine, Research Institute of Angiocardiology, Faculty of Medical Sciences, Kyushu University

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<jats:sec> <jats:title>Background:</jats:title> <jats:p>Dilated cardiomyopathy (DCM) is a life-threatening disease, resulting in refractory heart failure. An immune disorder underlies the pathophysiology associated with heart failure progression. Invariant natural killer T (iNKT) cell activation is a prospective therapeutic strategy for ischemic heart disease. However, its efficacy in nonischemic cardiomyopathy, such as DCM, remains to be elucidated, and the feasible modality for iNKT cell activation in humans is yet to be validated.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods:</jats:title> <jats:p> Dendritic cells isolated from human volunteers were pulsed with α-galactosylceramide ex vivo, which were used as α-galactosylceramide-pulsed dendritic cells (αGCDCs). We treated DCM mice harboring mutated troponin T <jats:sup>ΔK210/ΔK210</jats:sup> with αGCDCs and evaluated the efficacy of iNKT cell activation on heart failure in DCM mice. Furthermore, we investigated the molecular basis underlying its therapeutic effects in these mice and analyzed primary cardiac cells under iNKT cell-secreted cytokines. </jats:p> </jats:sec> <jats:sec> <jats:title>Results:</jats:title> <jats:p> The number of iNKT cells in the spleens of DCM mice was reduced compared with that in wild-type mice, whereas αGCDC treatment activated iNKT cells, prolonged survival of DCM mice, and prevented decline in the left ventricular ejection fraction for 4 weeks, accompanied by suppressed interstitial fibrosis. Mechanistically, αGCDC treatment suppressed TGF (transforming growth factor)-β signaling and expression of fibrotic genes and restored vasculature that was impaired in DCM hearts by upregulating angiopoietin 1 ( <jats:italic>Angpt1</jats:italic> ) expression. Consistently, IFNγ (interferon gamma) suppressed TGF-β-induced Smad2/3 signaling and the expression of fibrotic genes in cardiac fibroblasts and upregulated <jats:italic>Angpt1</jats:italic> expression in cardiomyocytes via Stat1. </jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions:</jats:title> <jats:p>Immunomodulatory cell therapy with αGCDCs is a novel therapeutic strategy for heart failure in DCM.</jats:p> </jats:sec>

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