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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...

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Autores principales: Tonne, Jason M., Sakuma, Toshie, Munoz-Gomez, Miguel, El Khatib, Moustafa, Barry, Michael A., Kudva, Yogish C., Ikeda, Yasuhiro
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2014
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.
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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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