| Increased Th17 rather than Th1 alloimmune response is associated with cardiac allograft vasculopathy after hypothermic preservation in the rat. | |
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MedLine Citation:
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PMID: 20591689 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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BACKGROUND: Preservation injury decreases patient survival and promotes the development of cardiac allograft vasculopathy. We investigated the sequential effects of hypothermic preservation on ischemia-reperfusion injury (IRI), subsequent innate immune activation, and adaptive immune response in rat cardiac allografts. METHODS: Allografts were transplanted from fully major histocompatibility complex-mismatched Dark Agouti to Wistar Furth rats without pre-operative hypothermia or after 4 hours of hypothermic preservation. Recipients received cyclosporine A immunosuppression. The allografts were recovered at 6 hours (n = 6, 7), 24 hours (n = 6), 10 days (n = 5), and 8 weeks (n = 5). Immunohistochemical, histologic, and reverse-transcription polymerase chain reaction analysis was performed. RESULTS: In IRI, significantly increased messenger RNA (mRNA) levels for Toll-like receptor 4, hyaluronan synthases (HAS)1-2 (p = 0.03), high-mobility group box 1 (p = 0.05), CD80/83 (p = 0.01, p = 0.048), and the cytokines tumor necrosis factor-alpha (p = 0.004), interferon-gamma (p = 0.012), and interleukin (IL)-6 (p = 0.019) were seen in allografts subjected to hypothermic preservation. During established alloimmune response, allografts subjected to hypothermic preservation expressed prominent infiltration of CD4+ T cells (p = 0.043) and dendritic cells (p = 0.029) and significantly up-regulated mRNA levels of CD80 (p = 0.036), chemokine (C-C motif) ligand 21 (p = 0.008), C-C chemokine receptor type 7 (p = 0.003), vascular endothelial growth factor-C (p = 0.016), and vascular endothelial growth factor receptor-3 (p = 0.02). These allografts also showed prominent mRNA upregulation of Foxp3 (p = 0.014), IL-17 (p = 0.038), and IL-23 (p = 0.043). Preservation significantly increased the incidence and intensity of allograft arteriosclerosis (p < 0.05) and cardiac fibrosis (p = 0.003) at 8 weeks. CONCLUSION: Our results demonstrate that preservation injury induced a cascade leading to an innate immune response that modulated the adaptive immune response towards Th17 rather than Th1 T-cell response in rat cardiac allografts and ultimately enhanced cardiac fibrosis and arterial occlusion. Our results also suggest that this immune response was not regulated by the calcineurin inhibitor cyclosporine A. |
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Authors:
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Simo O Syrjälä; Mikko A I Keränen; Raimo Tuuminen; Antti I Nykänen; Markku Tammi; Rainer Krebs; Karl B Lemström |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-06-29 |
Journal Detail:
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Title: The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Volume: 29 ISSN: 1557-3117 ISO Abbreviation: J. Heart Lung Transplant. Publication Date: 2010 Sep |
Date Detail:
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Created Date: 2010-08-23 Completed Date: 2010-12-30 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9102703 Medline TA: J Heart Lung Transplant Country: United States |
Other Details:
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Languages: eng Pagination: 1047-57 Citation Subset: IM |
Copyright Information:
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Copyright 2010 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved. |
Affiliation:
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Cardiopulmonary Research Group, Transplantation Laboratory, Haartman Institute, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland. simo.syrjala@helsinki.fi |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Acute Disease Animals Antigens, CD / genetics Chronic Disease Cyclosporine / therapeutic use Dendritic Cells / immunology Graft Rejection / epidemiology, immunology Heart Transplantation / immunology*, pathology Immunoglobulins / genetics Immunosuppressive Agents / therapeutic use Membrane Glycoproteins / genetics Organ Preservation / methods RNA, Messenger / genetics Rats Rats, Inbred Strains Rats, Inbred WF Reperfusion / methods Th1 Cells / immunology* Th17 Cells / immunology* Time Factors Transplantation, Homologous / immunology |
| Chemical | |
Reg. No./Substance:
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0/Antigens, CD; 0/CD83 antigen; 0/Immunoglobulins; 0/Immunosuppressive Agents; 0/Membrane Glycoproteins; 0/RNA, Messenger; 59865-13-3/Cyclosporine |
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