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Beta cell regeneration after single-round immunological destruction in a mouse model
AIMS/HYPOTHESIS: Achieving a better understanding of beta cell regeneration after immunological destruction is crucial for the development of immunotherapy approaches for type 1 diabetes. In previous type 1 diabetes models, sustained immune activation eliminates regenerating beta cells, thus limitin...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Berlin Heidelberg
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4287683/ https://www.ncbi.nlm.nih.gov/pubmed/25338552 http://dx.doi.org/10.1007/s00125-014-3416-4 |
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author | Tonne, Jason M. Sakuma, Toshie Munoz-Gomez, Miguel El Khatib, Moustafa Barry, Michael A. Kudva, Yogish C. Ikeda, Yasuhiro |
author_facet | Tonne, Jason M. Sakuma, Toshie Munoz-Gomez, Miguel El Khatib, Moustafa Barry, Michael A. Kudva, Yogish C. Ikeda, Yasuhiro |
author_sort | Tonne, Jason M. |
collection | PubMed |
description | AIMS/HYPOTHESIS: Achieving a better understanding of beta cell regeneration after immunological destruction is crucial for the development of immunotherapy approaches for type 1 diabetes. In previous type 1 diabetes models, sustained immune activation eliminates regenerating beta cells, thus limiting the study of the regenerative capacity of beta cells upon immunological destruction. Here, we employed an adeno-associated virus 8 (AAV8) vector for beta cell-targeted overexpression of a foreign antigen to induce single-round immunological destruction of existing beta cells. METHODS: Young and aged C57BL/6J mice were treated with AAV8 vectors expressing the foreign antigen luciferase. Islet inflammation and regeneration was observed at 3, 6, 10 and 22 weeks post-AAV delivery. RESULTS: In young C57BL/6J mice, robust humoral and cellular immune responses were developed towards antigen-expressing beta cells, leading to decreased beta cell mass. This was followed by beta cell mass replenishment, along with enhanced proliferation of insulin-positive cells, recruitment of nestin/CD34-positive endothelial cells, displacement of alpha cells and mobilisation of cytoplasmic neurogenin 3-positive cells. Mice with recovering beta cells showed normal or reduced fasting blood glucose levels and faster glucose clearance than controls. Although aged mice demonstrated similar responses to the treatment, they initially exhibited notable islet scarring and fluctuations in blood glucose levels, indicating that beta cell regeneration is slower in aged mice. CONCLUSIONS/INTERPRETATION: Our hit-and-run, beta cell-targeted antigen expression system provides an opportunity to monitor the impact of single-round immunological beta cell destruction in animals with diverse genetic backgrounds or ageing status. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00125-014-3416-4) contains peer-reviewed but unedited supplementary material, which is available to authorised users. |
format | Online Article Text |
id | pubmed-4287683 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Springer Berlin Heidelberg |
record_format | MEDLINE/PubMed |
spelling | pubmed-42876832015-01-15 Beta cell regeneration after single-round immunological destruction in a mouse model Tonne, Jason M. Sakuma, Toshie Munoz-Gomez, Miguel El Khatib, Moustafa Barry, Michael A. Kudva, Yogish C. Ikeda, Yasuhiro Diabetologia Article AIMS/HYPOTHESIS: Achieving a better understanding of beta cell regeneration after immunological destruction is crucial for the development of immunotherapy approaches for type 1 diabetes. In previous type 1 diabetes models, sustained immune activation eliminates regenerating beta cells, thus limiting the study of the regenerative capacity of beta cells upon immunological destruction. Here, we employed an adeno-associated virus 8 (AAV8) vector for beta cell-targeted overexpression of a foreign antigen to induce single-round immunological destruction of existing beta cells. METHODS: Young and aged C57BL/6J mice were treated with AAV8 vectors expressing the foreign antigen luciferase. Islet inflammation and regeneration was observed at 3, 6, 10 and 22 weeks post-AAV delivery. RESULTS: In young C57BL/6J mice, robust humoral and cellular immune responses were developed towards antigen-expressing beta cells, leading to decreased beta cell mass. This was followed by beta cell mass replenishment, along with enhanced proliferation of insulin-positive cells, recruitment of nestin/CD34-positive endothelial cells, displacement of alpha cells and mobilisation of cytoplasmic neurogenin 3-positive cells. Mice with recovering beta cells showed normal or reduced fasting blood glucose levels and faster glucose clearance than controls. Although aged mice demonstrated similar responses to the treatment, they initially exhibited notable islet scarring and fluctuations in blood glucose levels, indicating that beta cell regeneration is slower in aged mice. CONCLUSIONS/INTERPRETATION: Our hit-and-run, beta cell-targeted antigen expression system provides an opportunity to monitor the impact of single-round immunological beta cell destruction in animals with diverse genetic backgrounds or ageing status. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00125-014-3416-4) contains peer-reviewed but unedited supplementary material, which is available to authorised users. Springer Berlin Heidelberg 2014-10-23 2015 /pmc/articles/PMC4287683/ /pubmed/25338552 http://dx.doi.org/10.1007/s00125-014-3416-4 Text en © The Author(s) 2014 https://creativecommons.org/licenses/by/4.0/ Open Access This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited. |
spellingShingle | Article Tonne, Jason M. Sakuma, Toshie Munoz-Gomez, Miguel El Khatib, Moustafa Barry, Michael A. Kudva, Yogish C. Ikeda, Yasuhiro Beta cell regeneration after single-round immunological destruction in a mouse model |
title | Beta cell regeneration after single-round immunological destruction in a mouse model |
title_full | Beta cell regeneration after single-round immunological destruction in a mouse model |
title_fullStr | Beta cell regeneration after single-round immunological destruction in a mouse model |
title_full_unstemmed | Beta cell regeneration after single-round immunological destruction in a mouse model |
title_short | Beta cell regeneration after single-round immunological destruction in a mouse model |
title_sort | beta cell regeneration after single-round immunological destruction in a mouse model |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4287683/ https://www.ncbi.nlm.nih.gov/pubmed/25338552 http://dx.doi.org/10.1007/s00125-014-3416-4 |
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