Scott Fraser W, Rowsell Paul, Wang Gen-Sheng, Burghardt Karolina, Kolb Hubert, Flohé Stefanie
Molecular Medicine Program, Ottawa Health Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
Diabetes. 2002 Jan;51(1):73-8. doi: 10.2337/diabetes.51.1.73.
Disease development in diabetes-prone BB rats is modified by the type of diet fed after weaning. The aim of this investigation was to determine whether exposure during the first week of life to antigens from a known diabetes-promoting diet (NIH-07) could modify diabetes incidence and, if so, to what extent this occurs via alterations in systemic T-cell reactivity, gut cytokines, or islet infiltration. Diabetes-prone BB (BBdp) rats were hand-fed twice daily between age 4 and 7 days with vehicle, a hydrolyzed casein (HC)-based infant formula, Pregestimil (PG), PG + cereal-based NIH-07 diet, PG + lipopolysaccharides (LPS) or PG + LPS + silica. After weaning, they were fed either an NIH-07 diet or a semipurified HC (diabetes-retardant) diet until 150 days. In separate studies, 5-day-old BBdp rat pups were administered the aforementioned treatments, and expression of intestinal mRNA for gamma-interferon (IFN-gamma) or transforming growth factor-beta (TGF-beta) was quantified using reverse transcriptase-polymerase chain reaction. The effect of early oral treatment with NIH-07 or PG on systemic T-cell reactivity was evaluated using footpad swelling delayed-type hypersensitivity (DTH) and the popliteal lymph node assay. Oral exposure of neonates to a complex mixture of antigens from the diabetes-promoting diet delayed onset of diabetes (79 vs. 88 days) and prevented disease in approximately one-third of animals. A similar protective effect was seen for neonatal exposure to wheat gluten in animals subsequently weaned onto a semipurified wheat gluten diet. By contrast, LPS-treated neonates displayed more severe insulitis and developed diabetes at an increased rate, which was significantly suppressed by co-administration of silica particles. The protective effect of early exposure to diabetogenic diets was not associated with significant reduction of islet infiltration, and there was no impact on the DTH response to food antigens. However, whereas diabetes-resistant BBc rats developed systemic tolerance to NIH-07 antigens fed chronically, BBdp rats did not. The lack of effect of the early oral antigen regimen on the DTH reaction in the footpad, a classic Th1-mediated reaction, suggests little effect on systemic T-cell reactivity. However, local effects were observed in the small intestine. Oral exposure to diabetes-promoting food antigens or LPS downregulated the Th1 cytokine IFN-gamma and decreased the IFN-gamma/TGF-beta ratio. Thus, oral exposure to diabetes-promoting food antigens and immune modulators in neonates can modify diabetes expression in association with changes in local cytokine balance in the gut.
易患糖尿病的BB大鼠的疾病发展会因断奶后所喂饮食的类型而改变。本研究的目的是确定在生命的第一周接触来自已知促糖尿病饮食（NIH - 07）的抗原是否会改变糖尿病发病率，如果是，这种改变在多大程度上是通过全身T细胞反应性、肠道细胞因子或胰岛浸润的改变而发生的。在4至7日龄期间，对易患糖尿病的BB（BBdp）大鼠每日人工喂养两次，分别喂食赋形剂、以水解酪蛋白（HC）为基础的婴儿配方奶粉Pregestimil（PG）、PG + 基于谷物的NIH - 07饮食、PG + 脂多糖（LPS）或PG + LPS + 二氧化硅。断奶后，将它们喂食NIH - 07饮食或半纯化的HC（抗糖尿病）饮食直至150日龄。在单独的研究中，对5日龄的BBdp大鼠幼崽进行上述处理，使用逆转录聚合酶链反应定量γ - 干扰素（IFN - γ）或转化生长因子 - β（TGF - β）的肠道mRNA表达。使用足垫肿胀迟发型超敏反应（DTH）和腘窝淋巴结试验评估早期口服NIH - 07或PG对全身T细胞反应性的影响。新生儿口服促糖尿病饮食中的复杂抗原混合物可延迟糖尿病发病（79天对88天），并使约三分之一的动物预防疾病。在随后断奶至半纯化小麦麸质饮食的动物中，新生儿接触小麦麸质也观察到类似的保护作用。相比之下，LPS处理过的新生儿表现出更严重的胰岛炎，糖尿病发病率增加，而同时给予二氧化硅颗粒可显著抑制这种情况。早期接触致糖尿病饮食的保护作用与胰岛浸润的显著减少无关，并且对食物抗原的DTH反应没有影响。然而，抗糖尿病的BBc大鼠对长期喂食NIH - 07抗原产生了全身耐受性，而BBdp大鼠则没有。早期口服抗原方案对足垫DTH反应（一种典型的Th1介导反应）缺乏影响，表明对全身T细胞反应性影响很小。然而，在小肠中观察到了局部效应。口服促糖尿病食物抗原或LPS会下调Th1细胞因子IFN - γ，并降低IFN - γ/TGF - β比值。因此，新生儿口服促糖尿病食物抗原和免疫调节剂可通过肠道局部细胞因子平衡变化来改变糖尿病的表现。
