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Beta cell regeneration after single-round immunological destruction in a mouse model.

ABSTRACT: 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.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.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.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.

SUBMITTER: Tonne JM

PROVIDER: S-EPMC4287683 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Type-1 diabetes (T1D) is an autoimmune disease targeting insulin-producing beta cells, resulting in dependence on exogenous insulin. To date, significant efforts have been invested to develop immune-modulatory therapies for T1D treatment. Previously, IL-2 immunotherapy was demonstrated to prevent and reverse T1D at onset in the non-obese diabetic (NOD) mouse model, revealing potential as a therapy in early disease stage in humans. In the NOD model, IL-2 deficiency contributes to a loss of regulatory T cell function. This deficiency can be augmented with IL-2 or antibody bound to IL-2 (Ab/IL-2) therapy, resulting in regulatory T cell expansion and potentiation. However, an understanding of the mechanism by which reconstituted regulatory T cell function allows for reversal of diabetes after onset is not clearly understood. Here, we describe that Ab/IL-2 immunotherapy treatment, given at the time of diabetes onset in NOD mice, not only correlated with reversal of diabetes and expansion of Treg cells, but also demonstrated the ability to significantly increase beta cell proliferation. Proliferation appeared specific to Ab/IL-2 immunotherapy, as anti-CD3 therapy did not have a similar effect. Furthermore, to assess the effect of Ab/IL-2 immunotherapy well after the development of diabetes, we tested the effect of delaying treatment for 4 weeks after diabetes onset, when beta cells were virtually absent. At this late stage after diabetes onset, Ab/IL-2 treatment was not sufficient to reverse hyperglycemia. However, it did promote survival in the absence of exogenous insulin. Proliferation of beta cells could not account for this improvement as few beta cells remained. Rather, abnormal insulin and glucagon dual-expressing cells were the only insulin-expressing cells observed in islets from mice with established disease. Thus, these data suggest that in diabetic NOD mice, beta cells have an innate capacity for regeneration both early and late in disease, which is revealed through IL-2 immunotherapy.

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Beta cell regeneration after single-round immunological destruction in a mouse model.

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