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C5a Blockade Increases Regulatory T Cell Numbers and Protects Against Microvascular Loss and Epithelial Damage in Mouse Airway Allografts
Microvascular injury during acute rejection has been associated with massive infiltration of CD4(+) T effector cells, and the formation of complement products (C3a and C5a). Regulatory T cells (Tregs) are potent immunosuppressors of the adaptive immune system and have proven sufficient to rescue mic...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2018
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5976734/ https://www.ncbi.nlm.nih.gov/pubmed/29881374 http://dx.doi.org/10.3389/fimmu.2018.01010 |
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author | Khan, Mohammad Afzal Alanazi, Fatimah Ahmed, Hala Abdalrahman Vater, Axel Assiri, Abdullah Mohammed Broering, Dieter Clemens |
author_facet | Khan, Mohammad Afzal Alanazi, Fatimah Ahmed, Hala Abdalrahman Vater, Axel Assiri, Abdullah Mohammed Broering, Dieter Clemens |
author_sort | Khan, Mohammad Afzal |
collection | PubMed |
description | Microvascular injury during acute rejection has been associated with massive infiltration of CD4(+) T effector cells, and the formation of complement products (C3a and C5a). Regulatory T cells (Tregs) are potent immunosuppressors of the adaptive immune system and have proven sufficient to rescue microvascular impairments. Targeting C5a has been linked with improved microvascular recovery, but its effects on the Treg and T effector balance is less well known. Here, we demonstrate the impact of C5a blockade on Treg induction and microvascular restoration in rejecting mouse airway allografts. BALB/c→C57BL/6 allografts were treated with a C5a-neutralizing l-aptamer (10 mg/kg, i.p. at d0 and every second day thereafter), and allografts were serially monitored for Treg infiltration, tissue oxygenation (tpO(2)), microvascular blood flow, and functional microvasculature between donor and recipients during allograft rejection. We demonstrated that C5a blocking significantly leads to enhanced presence of Tregs in the allograft, reinstates donor–recipient functional microvasculature, improves tpO(2), microvascular blood flow, and epithelial repair, followed by an upregulation of IL-5, TGF-β, IL-10 vascular endothelial growth factor, and ANGPT1 gene expression, while it maintained a healthy epithelium and prevented subepithelial collagen deposition at d28 posttransplantation. Together, these data indicate that inhibition of C5a signaling has potential to preserve microvasculature and rescue allograft from a sustained hypoxic/ischemic phase, limits airway tissue remodeling through the induction of Treg-mediated immune tolerance. These findings may be useful in designing anti-C5a therapy in combination with existing immunosuppressive regimens to rescue tissue/organ rejection. |
format | Online Article Text |
id | pubmed-5976734 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-59767342018-06-07 C5a Blockade Increases Regulatory T Cell Numbers and Protects Against Microvascular Loss and Epithelial Damage in Mouse Airway Allografts Khan, Mohammad Afzal Alanazi, Fatimah Ahmed, Hala Abdalrahman Vater, Axel Assiri, Abdullah Mohammed Broering, Dieter Clemens Front Immunol Immunology Microvascular injury during acute rejection has been associated with massive infiltration of CD4(+) T effector cells, and the formation of complement products (C3a and C5a). Regulatory T cells (Tregs) are potent immunosuppressors of the adaptive immune system and have proven sufficient to rescue microvascular impairments. Targeting C5a has been linked with improved microvascular recovery, but its effects on the Treg and T effector balance is less well known. Here, we demonstrate the impact of C5a blockade on Treg induction and microvascular restoration in rejecting mouse airway allografts. BALB/c→C57BL/6 allografts were treated with a C5a-neutralizing l-aptamer (10 mg/kg, i.p. at d0 and every second day thereafter), and allografts were serially monitored for Treg infiltration, tissue oxygenation (tpO(2)), microvascular blood flow, and functional microvasculature between donor and recipients during allograft rejection. We demonstrated that C5a blocking significantly leads to enhanced presence of Tregs in the allograft, reinstates donor–recipient functional microvasculature, improves tpO(2), microvascular blood flow, and epithelial repair, followed by an upregulation of IL-5, TGF-β, IL-10 vascular endothelial growth factor, and ANGPT1 gene expression, while it maintained a healthy epithelium and prevented subepithelial collagen deposition at d28 posttransplantation. Together, these data indicate that inhibition of C5a signaling has potential to preserve microvasculature and rescue allograft from a sustained hypoxic/ischemic phase, limits airway tissue remodeling through the induction of Treg-mediated immune tolerance. These findings may be useful in designing anti-C5a therapy in combination with existing immunosuppressive regimens to rescue tissue/organ rejection. Frontiers Media S.A. 2018-05-24 /pmc/articles/PMC5976734/ /pubmed/29881374 http://dx.doi.org/10.3389/fimmu.2018.01010 Text en Copyright © 2018 Khan, Alanazi, Ahmed, Vater, Assiri and Broering. https://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology Khan, Mohammad Afzal Alanazi, Fatimah Ahmed, Hala Abdalrahman Vater, Axel Assiri, Abdullah Mohammed Broering, Dieter Clemens C5a Blockade Increases Regulatory T Cell Numbers and Protects Against Microvascular Loss and Epithelial Damage in Mouse Airway Allografts |
title | C5a Blockade Increases Regulatory T Cell Numbers and Protects Against Microvascular Loss and Epithelial Damage in Mouse Airway Allografts |
title_full | C5a Blockade Increases Regulatory T Cell Numbers and Protects Against Microvascular Loss and Epithelial Damage in Mouse Airway Allografts |
title_fullStr | C5a Blockade Increases Regulatory T Cell Numbers and Protects Against Microvascular Loss and Epithelial Damage in Mouse Airway Allografts |
title_full_unstemmed | C5a Blockade Increases Regulatory T Cell Numbers and Protects Against Microvascular Loss and Epithelial Damage in Mouse Airway Allografts |
title_short | C5a Blockade Increases Regulatory T Cell Numbers and Protects Against Microvascular Loss and Epithelial Damage in Mouse Airway Allografts |
title_sort | c5a blockade increases regulatory t cell numbers and protects against microvascular loss and epithelial damage in mouse airway allografts |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5976734/ https://www.ncbi.nlm.nih.gov/pubmed/29881374 http://dx.doi.org/10.3389/fimmu.2018.01010 |
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