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Modeling the onset of type 1 diabetes Kublik, Richard Alexander

Abstract

A neonatal wave of apoptosis (programmed cell death) occurs normally in the pancreatic β-cells of mice and rats. Previous collaborative work by members of Diane T Finegood's experimental lab at Simon Fraser University and Leah Edelstein-Keshet's mathematical biology group at the University of British Columbia demonstrated that macrophages from non-obese diabetic (NOD) mice become activated more slowly and engulf apoptotic cells at a lower rate than macrophages from control (Balb/c) mice. It has been hypothesized that this low clearance could result in secondary necrosis of the β-cells, escalating inflammation and the self-antigen presentation that later triggers autoimmune, type 1 diabetes. We here investigate whether this hypothesis could offer a reasonable and simplified explanation for the onset of type 1 diabetes in NOD mice. We quantify variants of the Copenhagen model, developed by Freiesleben De Blasio et al (1999, Diabetes 48, 1677), based on parameters from NOD and Balb/c experimental data. We demonstrate that the original Copenhagen model fails to explain observed phenomena within a reasonable range of parameter values, predicting an unrealistic all-or-none disease occurrence in both strains. However, if we assume that the activated macrophages produce harmful cytokines only when engulfing necrotic (but not apoptotic) cells, then the revised model becomes qualitatively and quantitatively reasonable. Further, we show that known differences between NOD and Balb/c mouse macrophages kinetics are large enough to account for the fact that an apoptotic wave can trigger escalating inflammatory response in NOD, but not Balb/c mice. In Balb/c mice, macrophages clear the apoptotic wave so efficiently, that chronic inflammation is prevented.

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