Gut Involvement in NOD Mouse Diabetes

The non obese diabetic (NOD) mouse is a very well studied model of autoimmune diabetes. NOD mice develop insulitis, an early infiltration of leukocytes into the pancreas that leads to inflammatory lesions within the islets. In NOD mice, it has been shown that diet modifies the incidence of the disease. In particular, the diabetogenic agents come from the plant protein fraction of the natural food; cereal and soy bean proteins remain the major identified diabetogenic food components. More recently, it was shown that the gluten-free diet both delayed and prevented diabetes onset in NOD mice that had never been exposed to gluten. Compelling evidences of gut immune system involvement in diabetes is also provided by this model. Lymphocytes expressing mucosal adhesion molecules have been found to infiltrate the islets, while MadCAM blockage inhibits the development of diabetes; furthermore, diabetes has been shown to be transferred with mesenteric lymph nodes cells, at the age of 3 months the most diabetogenic cells being in the GALT (Gut Associated Lymphoid Tissue). Mice fed wheat containing diet have not only a higher incidence of diabetes, but also signs of small intestinal enteropathy and higher mucosal levels of proinflammatory cytokines. They show significant levels of serum antitTG antibodies, and single-chain antibody fragments to mouse tTG have been isolated mainly from the antibody libraries made from intestinal lymphocytes. While there is little doubt about the involvement of the intestinal immune response in the pathogenesis of diabetes, it is still unclear if dietary proteins (e.g. wheat) primarily trigger the inflammatory and then the autoimmune process in genetically prone individuals. Alternatively, dietary proteins could act on an already inflamed mucosa, because structurally more leaky or because the site of an ongoing autoimmune process, causing further damage.