T lymphocytes and B lymphocytes specific for other antigens are not activated in the current model. CD4+ regulatory T lymphocytes.  Innate (or natural) regulatory T lymphocytes (iTregs), representing

CD4+CD25+ T lymphocytes, mTOR inhibitor are modelled as a distinct population of thymic-derived cells, distinguished from the aforementioned aTregs by not requiring further differentiation to express regulatory activity [52]. Once activated via presentation of autoantigen on MHC class II molecules (MHCII antigen), regulatory T lymphocytes exhibit both cell contact-mediated and cytokine-mediated immunosuppressive activity [46,53,54]. CD8+ T lymphocytes.  CD8+ T lymphocytes in the model are initially activated by MHCI-antigen in the PLN, with help provided Small molecule library by activated CD4+ T lymphocytes [55–58]. Acquired cytotoxic effector activity includes both cell contact- and cytokine-mediated mechanisms [59,60]. B lymphocytes.  B lymphocytes in the model interact with DCs, natural killer (NK) cells and T lymphocytes. They differentiate (in the PLN), present antigen to CD4+ and CD8+ T lymphocytes and produce cytokines and autoantibodies [61–63]. Autoantibodies form immune complexes, influencing antigen uptake

[26,64]. NK cells.  On the recommendation of the scientific advisory board, NK cells were included in the model based on a high degree of scientific interest and investigation [65–68]. Because the data characterizing NK cells in type 1 diabetes and their relative role in disease are sparse relative to other cell types, the use of the NK cell module is optional (i.e. it can be omitted from the virtual mouse simulations). Inclusion of the NK cell module may be used to explore specific hypotheses on the role of NK cells in disease. Arachidonate 15-lipoxygenase Activation of NK cells in the model is mediated by DCs and B lymphocytes and is regulated further by cytokines and co-stimulatory molecules [69–74]. Effector activities include cytokine synthesis and killing of immature

DCs and β cells [75,76]. Blood glucose.  The level of blood glucose in the model is regulated by insulin-dependent and insulin-independent mechanisms, based on deviations of insulin and glucose from their basal levels [77,78]. Dietary glucose intake is assumed to be constant and implicitly accounted for in the basal glucose level. Gut and gut-associated lymphoid tissue.  The gut and gut-associated lymphoid tissue (GALT) were built to investigate the role of local immune activity on the efficacy of oral insulin therapy. The gut tissue in the model is simplified to include only DCs. The GALT includes all the biological components present in the modelled PLN. Following the design phase, the components of the model were represented mathematically. As illustrated in Fig.