title: Beta cell regeneration after single-round immunological destruction in a mouse model.
abstract: OBJECTIVE
  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
  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.
authors.affiliation: Department of Molecular Medicine, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN, 55905, USA.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Tonne
authors.forename: Toshie
authors.initials: T
authors.lastname: Sakuma
authors.forename: Miguel
authors.initials: M
authors.lastname: Munoz-Gomez
authors.forename: Moustafa
authors.initials: M
authors.lastname: El Khatib
authors.forename: Michael A
authors.initials: MA
authors.lastname: Barry
authors.forename: Yogish C
authors.initials: YC
authors.lastname: Kudva
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Ikeda
mesh_terms: D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D000229:Dependovirus; D003922:Diabetes Mellitus, Type 1 / Q000473:pathology*; D004195:Disease Models, Animal; D005822:Genetic Vectors; D007166:Immunosuppressive Agents / Q000494:pharmacology; D050417:Insulin-Secreting Cells / Q000276:immunology / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010322:Parvoviridae Infections; D012038:Regeneration / Q000187:drug effects / Q000276:immunology*
chemical_list: D007166:Immunosuppressive Agents