The importance of the Non Obese Diabetic (NOD) mouse model in autoimmune diabetes

Abstract

Type 1 Diabetes (T1D) is an autoimmune disease characterized by the pancreatic infiltration of immune cells resulting in T cell-mediated destruction of the insulin-producing beta cells. The successes of the Non-Obese Diabetic (NOD) mouse model have come in multiple forms including identifying key genetic and environmental risk factors e.g. Idd loci and effects of microorganisms including the gut microbiota, respectively, and how they may contribute to disease susceptibility and pathogenesis. Furthermore, the NOD model also provides insights into the roles of the innate immune cells as well as the B cells in contributing to the T cell-mediated disease. Unlike many autoimmune disease models, the NOD mouse develops spontaneous disease and has many similarities to human T1D. Through exploiting these similarities many targets have been identified for immune-intervention strategies. Although many of these immunotherapies did not have a significant impact on human T1D, they have been shown to be effective in the NOD mouse in early stage disease, which is not equivalent to trials in newly-diagnosed patients with diabetes. However, the continued development of humanized NOD mice would enable further clinical developments, bringing T1D research to a new translational level. Therefore, it is the aim of this review to discuss the importance of the NOD model in identifying the roles of the innate immune system and the interaction with the gut microbiota in modifying diabetes susceptibility. In addition, the role of the B cells will also be discussed with new insights gained through B cell depletion experiments and the impact on translational developments. Finally, this review will also discuss the future of the NOD mouse and the development of humanized NOD mice, providing novel insights into human T1D.

Keywords: B cells; Gut microbiota; Humanized mice; NOD; Type 1 diabetes.

FIGURE 1. FACTORS INFLUENCING THE HOST MICROBIOTA AND DIABETES

The gut microbiota has been shown to have a significant effect on the development of the immune system and vice versa in modifying risk of developing autoimmunity. While the bacteria can be directly influenced through the use of antibiotics and probiotics, the environmental niche in which they reside is also important. Environmental factors including sex hormones and those involved in metabolism can contribute to changes in the bacterial composition. Furthermore, the genetics of the host and the ability of the immune system to respond to the bacteria are also influential factors in shaping the gut microbiome. By altering the gut microbiota, it is possible to alter the antigens presented to the immune system and the context in which those antigens are presented i.e. in proinflammatory vs normal homeostatic turnover, the immune system can respond differently either protecting from or promoting autoimmunity. Therefore targeting different parts of this interactive network may enable tolerance and protection from disease.

FIGURE 2. TLR AND NLR SIGNALING PATHWAYS

Pathogen-associated molecular patterns (e.g. LPS, Flagellin, bacterial peptidoglycan) bind to their specific TLR and mediate downstream effects, signaling through MyD88 and subsequently inducing proinflammatory cytokines. TLR3 and sometime TLR4 can also signal through TRIF upon binding to their ligand within the endosome, inducing proinflammatory cytokines and type I interferons to protect further cells from infection. In addition TLR7, 8 and 9 can also bind their ligand in the endosome and induce type I interferons. To help regulate these signaling pathways, molecules such as IRAK-M are present to inhibit MyD88 signaling and prevent or down-regulate the level of inflammation. NLR signaling is believed to induce an additive response to the TLR signaling pathway. Similarly to the TLR signaling pathway, bacterial pathogen-associated molecular patterns can enter the cell and activate the cytosolic NLR signaling molecules such as NOD1/2, NLRP3 and NLRC4 (IPAF). These NLR molecules require the formation of inflammasomes (multi-subunit proteins interacting) in order to mediate their effects. While these pathways promote proinflammatory cytokines mediated through NF-KB, they also induce the activation of caspase 1, which in turn cleaves pro-IL1beta and pro-IL18 into their activated forms.

FIGURE 2. TLR AND NLR SIGNALING PATHWAYS

Pathogen-associated molecular patterns (e.g. LPS, Flagellin, bacterial peptidoglycan) bind to their specific TLR and mediate downstream effects, signaling through MyD88 and subsequently inducing proinflammatory cytokines. TLR3 and sometime TLR4 can also signal through TRIF upon binding to their ligand within the endosome, inducing proinflammatory cytokines and type I interferons to protect further cells from infection. In addition TLR7, 8 and 9 can also bind their ligand in the endosome and induce type I interferons. To help regulate these signaling pathways, molecules such as IRAK-M are present to inhibit MyD88 signaling and prevent or down-regulate the level of inflammation. NLR signaling is believed to induce an additive response to the TLR signaling pathway. Similarly to the TLR signaling pathway, bacterial pathogen-associated molecular patterns can enter the cell and activate the cytosolic NLR signaling molecules such as NOD1/2, NLRP3 and NLRC4 (IPAF). These NLR molecules require the formation of inflammasomes (multi-subunit proteins interacting) in order to mediate their effects. While these pathways promote proinflammatory cytokines mediated through NF-KB, they also induce the activation of caspase 1, which in turn cleaves pro-IL1beta and pro-IL18 into their activated forms.