Oral tolerance and immune mechanisms in food-induced diabetes.

Diet controls $\sim$80% of type-I (insulin-dependent) diabetes in the diabetes-prone BioBreeding (BBdp) rat. This study was designed to define the relationship among diet, the gut immune system and the pancreas. BB rats were fed either a diabetogenic NIH-07 (NIH) diet or the diabetes protective, hydrolysed casein (HC) diet. Bovine serum albumin (BSA), ovalbumin (OVA), sheep red blood cells (SRBC) and NIH were given by gavage daily for 5 days. Both BBdp and the diabetes resistant BBc rat when fed NIH became unresponsive in antibody production to NIH antigens. None of the other oral antigen treatments induced tolerance. In delayed-type hypersensitivity (DTH) reactions, footpad injection of NIH resulted in lower DTH reactions and less increase in popliteal lymph node weight when animals were fed NIH than HC. We conclude that oral tolerance, both cell-mediated and humoral, to diabetogenic antigens is inducible in both strains of BB rats. This required daily feeding unlike in other rat strains. The depressed DTH reaction in the animals fed NIH indicates no link between the systemic Th1 DTH reaction to NIH and the Th1 food-induced diabetogenesis. Neonatal intrathymic injection of autoclaved NIH did not affect diabetes incidence, suggesting systemic exposure to these food antigens was not protective. Feeding neonatal BBdp rats a diabetogenic diet between 4 and 7d of age significantly delayed diabetes and reduced incidence. This effect was seen with the NIH diet and its diabetogenic component, wheat gluten. We conclude that early exposure to food diabetogens is protective against food-induced diabetes, indicating a crucial link between the local gut immune system and autoimmunity against pancreatic $\beta$ cells