, Foster City, CA, USA). Assumptions and formulation.  The PLN and each islet are assumed to be well-mixed, spatially homogenous compartments. Each islet bin, as described above, contains the same model architecture. Differences in simulated behaviours in islets of different bins result from sequential and progressive lymphocyte infiltration of different islets and islet bins, leading to different

degrees of accumulated infiltrate, see more local inflammation and damage at a given time. Common functions represented in all compartments include mediator synthesis, cellular proliferation, apoptosis and activation. Each of these functions are regulated by cell contact and soluble mediators with the following basic approach: (i) a baseline rate is Decitabine in vitro assigned if data suggest a constitutive activity; (ii) additional stimulatory effects are assumed to be additive; (iii) regulators that synergize or amplify the impact of another are treated as potentiating them and represented as having multiplicative effects; (iv) inhibitory

effects are represented as fractional reductions in baseline and/or stimulated effects as indicated by the data; and (v) an upper limit may be imposed, such as when the rate is proportional to the fraction of cells involved (e.g. proliferation) and saturates at 100% involvement. The likelihood of cell contact within a compartment is a function of the relative numbers of each cell type within the total cellular population. Mediator concentrations in each compartment are a function of the synthesis rate (i.e. ng/1e6 cells/h), the number of mediator-producing cells, mediator half-life and the compartment volume. Because the effect of each regulator

is dependent on its concentration/activity, ADAMTS5 a standard dose–response curve was employed to describe the relationship between the regulator and its effects (Fig. 3). Published data were used to define the effective concentration range and the maximum effect. If the effective concentration range had not been published, the available data were used to define the saturating concentration and a three-log range of dose-sensitivity is assumed. Parameterization.  Parameter values were derived directly from (or calculated to be in agreement with) published data wherever quantitative data were available. Preference was given to NOD mouse data. If unavailable, data from other mouse strains, other animal species or human cells were used. The determination of the rate of tumour necrosis factor (TNF)-α synthesis by activated CD8+ T lymphocytes from Utsugi et al. [79] is a relevant illustration of data usage. They reported TNF-α production by NOD CD8+ T cell clones stimulated with islet cells. In all similar cases where parameters were extracted/calculated from specific literature, the references are cited in the location within the model where the parameter was used. Thus, all directly derived parameters are referenced.