Abstract
Aims/hypothesisAchieving 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.MethodsYoung 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.ResultsIn 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/interpretationOur 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 materialThe 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.
Highlights
In individuals susceptible to type 1 diabetes, exposure to environmental triggers is thought to induce abnormal activation of cellular and humoral immune responses against beta cells, leading to the initiation of beta cell destruction
The spontaneous recovery of beta cell function in some patients with early-onset type 1 diabetes suggests that beta cells retain their regenerative capacity in type 1 diabetes [5]
Primarily because of the technical difficulties involved in monitoring beta cell mass in type 1 diabetic patients, the capacity for beta cell regeneration following immunological beta cell destruction has not been determined
Summary
In individuals susceptible to type 1 diabetes, exposure to environmental triggers is thought to induce abnormal activation of cellular and humoral immune responses against beta cells, leading to the initiation of beta cell destruction. Several studies have demonstrated direct evidence of beta cell proliferation in early-onset type 1 diabetes [3, 4]. The spontaneous recovery of beta cell function in some patients with early-onset type 1 diabetes suggests that beta cells retain their regenerative capacity in type 1 diabetes [5]. Primarily because of the technical difficulties involved in monitoring beta cell mass in type 1 diabetic patients, the capacity for beta cell regeneration following immunological beta cell destruction has not been determined
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