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Alpha 1 Antitrypsin Gene Therapy Extends the Lifespan of Lupus-Prone Mice
Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease characterized by high levels of pathogenic autoantibodies and tissue damage. Multiple studies showed that dendritic cell (DC) activation plays a critical role in SLE pathogenesis. Human alpha 1 antitrypsin (hAAT) is a serine pr...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society of Gene & Cell Therapy
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6258868/ https://www.ncbi.nlm.nih.gov/pubmed/30547047 http://dx.doi.org/10.1016/j.omtm.2018.10.007 |
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author | Elshikha, Ahmed Samir Yuan, Ye Lu, Yuanqing Chen, Mong-Jen Abboud, Georges Akbar, Mohammad Ahsanul Plate, Henrike Wolney, Hedwig Hoffmann, Tanja Tagari, Eleni Zeumer, Leilani Morel, Laurence Song, Sihong |
author_facet | Elshikha, Ahmed Samir Yuan, Ye Lu, Yuanqing Chen, Mong-Jen Abboud, Georges Akbar, Mohammad Ahsanul Plate, Henrike Wolney, Hedwig Hoffmann, Tanja Tagari, Eleni Zeumer, Leilani Morel, Laurence Song, Sihong |
author_sort | Elshikha, Ahmed Samir |
collection | PubMed |
description | Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease characterized by high levels of pathogenic autoantibodies and tissue damage. Multiple studies showed that dendritic cell (DC) activation plays a critical role in SLE pathogenesis. Human alpha 1 antitrypsin (hAAT) is a serine proteinase inhibitor with potent anti-inflammatory and cytoprotective properties. In this study, we first examined the effects of hAAT on the functions of DCs from lupus-prone mice, and we showed that hAAT treatment efficiently inhibited CpG- (TLR9 agonist) induced activation of bone marrow-derived conventional and plasmacytoid DCs as well as the production of pro-inflammatory cytokines. The hAAT treatment also attenuated DC help for B cell proliferation and immunoglobulin M (IgM) production. We next tested the protective effect of hAAT protein and gene therapy using recombinant adeno-associated virus 8 (rAAV8-CB-hAAT) in a spontaneous lupus mouse model, and we showed that both treatments decreased autoantibody levels. Importantly, rAAV8-CB-hAAT did not induce an immune response to its transgene product (hAAT), but it showed more pronounced therapeutic effects in reducing urine protein levels and extending the lifespan of these mice. These results indicate that AAT has therapeutic potential in the treatment of SLE in humans. |
format | Online Article Text |
id | pubmed-6258868 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | American Society of Gene & Cell Therapy |
record_format | MEDLINE/PubMed |
spelling | pubmed-62588682018-12-13 Alpha 1 Antitrypsin Gene Therapy Extends the Lifespan of Lupus-Prone Mice Elshikha, Ahmed Samir Yuan, Ye Lu, Yuanqing Chen, Mong-Jen Abboud, Georges Akbar, Mohammad Ahsanul Plate, Henrike Wolney, Hedwig Hoffmann, Tanja Tagari, Eleni Zeumer, Leilani Morel, Laurence Song, Sihong Mol Ther Methods Clin Dev Article Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease characterized by high levels of pathogenic autoantibodies and tissue damage. Multiple studies showed that dendritic cell (DC) activation plays a critical role in SLE pathogenesis. Human alpha 1 antitrypsin (hAAT) is a serine proteinase inhibitor with potent anti-inflammatory and cytoprotective properties. In this study, we first examined the effects of hAAT on the functions of DCs from lupus-prone mice, and we showed that hAAT treatment efficiently inhibited CpG- (TLR9 agonist) induced activation of bone marrow-derived conventional and plasmacytoid DCs as well as the production of pro-inflammatory cytokines. The hAAT treatment also attenuated DC help for B cell proliferation and immunoglobulin M (IgM) production. We next tested the protective effect of hAAT protein and gene therapy using recombinant adeno-associated virus 8 (rAAV8-CB-hAAT) in a spontaneous lupus mouse model, and we showed that both treatments decreased autoantibody levels. Importantly, rAAV8-CB-hAAT did not induce an immune response to its transgene product (hAAT), but it showed more pronounced therapeutic effects in reducing urine protein levels and extending the lifespan of these mice. These results indicate that AAT has therapeutic potential in the treatment of SLE in humans. American Society of Gene & Cell Therapy 2018-10-18 /pmc/articles/PMC6258868/ /pubmed/30547047 http://dx.doi.org/10.1016/j.omtm.2018.10.007 Text en © 2018 The Authors http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Elshikha, Ahmed Samir Yuan, Ye Lu, Yuanqing Chen, Mong-Jen Abboud, Georges Akbar, Mohammad Ahsanul Plate, Henrike Wolney, Hedwig Hoffmann, Tanja Tagari, Eleni Zeumer, Leilani Morel, Laurence Song, Sihong Alpha 1 Antitrypsin Gene Therapy Extends the Lifespan of Lupus-Prone Mice |
title | Alpha 1 Antitrypsin Gene Therapy Extends the Lifespan of Lupus-Prone Mice |
title_full | Alpha 1 Antitrypsin Gene Therapy Extends the Lifespan of Lupus-Prone Mice |
title_fullStr | Alpha 1 Antitrypsin Gene Therapy Extends the Lifespan of Lupus-Prone Mice |
title_full_unstemmed | Alpha 1 Antitrypsin Gene Therapy Extends the Lifespan of Lupus-Prone Mice |
title_short | Alpha 1 Antitrypsin Gene Therapy Extends the Lifespan of Lupus-Prone Mice |
title_sort | alpha 1 antitrypsin gene therapy extends the lifespan of lupus-prone mice |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6258868/ https://www.ncbi.nlm.nih.gov/pubmed/30547047 http://dx.doi.org/10.1016/j.omtm.2018.10.007 |
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