The Role of NOD Mice in Type 1 Diabetes Research: Lessons from the Past and Recommendations for the Future

Abstract

For more than 35 years, the NOD mouse has been the primary animal model for studying autoimmune diabetes. During this time, striking similarities to the human disease have been uncovered. In both species, unusual polymorphisms in a major histocompatibility complex (MHC) class II molecule confer the most disease risk, disease is caused by perturbations by the same genes or different genes in the same biological pathways and that diabetes onset is preceded by the presence of circulating autoreactive T cells and autoantibodies that recognize many of the same islet antigens. However, the relevance of the NOD model is frequently challenged due to past failures translating therapies from NOD mice to humans and because the appearance of insulitis in mice and some patients is different. Nevertheless, the NOD mouse remains a pillar of autoimmune diabetes research for its usefulness as a preclinical model and because it provides access to invasive procedures as well as tissues that are rarely procured from patients or controls. The current article is focused on approaches to improve the NOD mouse by addressing reasons why immune therapies have failed to translate from mice to humans. We also propose new strategies for mixing and editing the NOD genome to improve the model in ways that will better advance our understanding of human diabetes. As proof of concept, we report that diabetes is completely suppressed in a knock-in NOD strain with a serine to aspartic acid substitution at position 57 in the MHC class II Aβ. This supports that similar non-aspartic acid substitutions at residue 57 of variants of the human class II HLA-DQβ homolog confer diabetes risk.

A comprehensive and comparative phenotypic analysis of the collaborative founder strains identifies new and known phenotypes

“…Intraperitoneal glucose tolerance tests were performed at the age of 13-14 weeks. The results confirmed several well-known strain-specific characteristics, such as impaired glucose tolerance in NZO/HILtJ and NOD/ShiLtJ mice (Chen et al 2018;Kleinert et al 2018) and references therein) (GMC11, data not shown). In contrast, 129S1/SvImJ mice showed very low basal fasting glucose levels and low AUC values, which is in line with the observation of low endogenous glucose production in fasting 129S1/SvImJ mice (Burgess et al 2005).…”

Immune cell trafficking to the islets during type 1 diabetes

“…There are many other chemokines that probably play redundant roles in the recruitment of T cells to the islets, including CXCL16 and its receptor CXCR6. This chemokine ligand-receptor pair is of particular interest in T1D, as CXCL16 is a potential candidate gene for the Idd4 T1D risk locus in mice, and CXCR6 is located within the IDDM22 T1D risk locus in humans [93][94][95][96]. In our work, CXCR6 was the highest chemokine receptor mRNA transcript expressed in islet T cells, and CXCL16 was the third highest expressed chemokine transcript in islet CD11c + cells [13].…”

Preclinical evaluation of antigen-specific nanotherapy based on phosphatidylserine-liposomes for type 1 diabetes

“…A previous work demonstrated the therapeutic potential of PS-liposomes encapsulating insulin peptidesas a main autoantigen in T1Dto prevent T1D in an experimental model of the disease, the Non-Obese Diabetic (NOD) mouse [8]. The NOD mouse, developed in 1980 [9] is considered the 'gold-standard' model for the study of T1D [10]. These mice develop T1D spontaneously around 12 weeks of age, after the immune-mediated destruction of insulin-producing b cells, commonly called insulitis.…”