Animal Models of Spontaneous Autoimmune Disease

The nonobese diabetic (NOD) mouse represents probably the best spontaneous model for a human autoimmune disease. It has provided not only essential information on type 1 diabetes (T1D) pathogenesis, but also valuable insights into mechanisms of immunoregulation and tolerance. Importantly, it allows testing of immunointervention strategies potentially applicable to man. The fact that T1D incidence in the NOD mouse is sensitive to environmental conditions, and responds, sometimes dramatically, to immunomanipulation, does not represent a limit of the model, but is likely to render it even more similar to its human counterpart. In both cases, macrophages, dendritic cells, CD4+, CD8+, and B cells are present in the diseased islets. T1D is a polygenic disease, but, both in human and in NOD mouse T1D, the primary susceptibility gene is located within the MHC. On the other hand, T1D incidence is significantly higher in NOD females, although insulitis is similar in both sexes, whereas in humans, T1D occurs with about equal frequency in males and females. In addition, NOD mice have a more widespread autoimmune disorder, which is not the case in the majority of human T1D cases. Despite these differences, the NOD mouse remains the most representative model of human T1D, with similarities also in the putative target autoantigens, including glutamic acid decarboxylase IA-2, and insulin.