Suppression of insulitis in non-obese diabetic (NOD) mice by oral insulin administration is associated with selective expression of interleukin-4 and -10, transforming growth factor-beta, and prostaglandin-E.
Suppression of insulitis in non-obese diabetic (NOD) mice by oral insulin administration is associated with selective expression of interleukin-4 and -10, transforming growth factor-beta, and prostaglandin-E.
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发表时间：
1995-11
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通讯作者：
Wayne W. Hancock;Malu Polanski;J. Zhang;N. Blogg;Howard L. Weiner
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作者：
Wayne W. Hancock;Malu Polanski;J. Zhang;N. Blogg;Howard L. Weiner
在几种动物模型中，口服自身抗原可抑制自身免疫的发展，并且正在多发性硬化症和类风湿性关节炎等自身免疫性疾病患者的临床试验中进行测试。非肥胖型糖尿病（NOD）小鼠在15 ~ 20周龄时，单核细胞（MNC）浸润朗格汉斯胰岛并破坏产生胰岛素的β细胞后，自发发展为胰岛素依赖型糖尿病。我们之前已经证明，口服胰岛素可以抑制NOD小鼠的胰岛素炎和糖尿病的发展。口服胰岛素对血糖没有代谢作用。通过过继转移和T细胞耗竭实验表明，口服胰岛素通过T细胞依赖机制介导其作用，但其机制尚未得到充分探讨。我们现在报告了NOD小鼠中与糖尿病发展相关的细胞和细胞因子的一系列分析，并将其与喂食马胰岛素或对照蛋白（卵清蛋白）的动物的发现进行了对比。试验动物从5周龄开始，每周饲喂2次，每次1 mg，连续5周。初代或卵清蛋白喂养NOD小鼠在10周时出现明显的胰岛素炎，此时观察到密集的胰岛周围和胰岛内MNC浸润。单克隆抗体免疫组织学研究显示，浸润的MNC主要由CD4+ T细胞（约占白细胞的75%）和少量巨噬细胞和CD8+ T细胞组成。这些细胞表现出免疫激活的证据，表达白细胞介素-2 （IL-2R）受体和Th1细胞因子；观察到ifn - γ和肿瘤坏死因子- α的密集标记，加上少量的IL-2。MNC缺乏IL-4、IL-10、前列腺素- e或转化生长因子- β的标记。相比之下，在10周时，注射胰岛素的NOD小鼠的胰腺组织显示出明显减少的胰岛素炎，残留的MNC虽然仍然主要是CD4+ T细胞和巨噬细胞，但显示出IL-4、IL-10、前列腺素- e和转化生长因子- β的密集标记，并且缺乏IL-2、ifn - γ或肿瘤坏死因子- α。这些数据表明，口服胰岛素通过在靶器官内产生精心制作免疫调节细胞因子的细胞，并将细胞因子表达的平衡从Th1模式转变为Th2模式，从而影响NOD小鼠糖尿病的发展。
Oral administration of autoantigens suppresses development of autoimmunity in several animal models, and is being tested in clinical trials in patients with autoimmune diseases such as multiple sclerosis and rheumatoid arthritis. Non-obese diabetic (NOD) mice spontaneously develop insulin-dependent diabetes mellitus at 15 to 20 weeks of age, after mononuclear cell (MNC) infiltration of the pancreatic islets of Langerhans and destruction of insulin-producing beta cells. We have previously shown that oral administration of insulin suppresses insulitis and development of diabetes in the NOD mouse. Oral insulin has no metabolic effect on blood glucose. Oral insulin mediates its effect through a T cell-dependent mechanism as shown by adoptive transfer and T cell depletion experiments, but the mechanisms responsible have not been fully explored. We now report a serial analysis of the cells and cytokines associated with development of diabetes in NOD mice, and contrast this with the findings in animals fed equine insulin or a control protein (ovalbumin). Animals were fed 1 mg twice a week for 5 weeks, beginning at 5 weeks of age. Marked insulitis in naive or ovalbumin-fed NOD mice occurred at 10 weeks, at which time a dense peri-islet and intra-islet MNC infiltration was observed. Immunohistological studies using monoclonal antibodies showed that infiltrating MNC consisted mainly of CD4+ T cells ( > 75% of leukocytes) plus smaller numbers of macrophages and CD8+ T cells. These cells displayed evidence of immune activation with expression of receptors for interleukin-2 (IL-2R) plus Th1 cytokines; dense labeling for IFN-gamma and tumor necrosis factor-alpha, plus lesser amounts of IL-2, was observed. MNC lacked labeling for IL-4, IL-10, prostaglandin-E, or transforming growth factor-beta. By contrast, at 10 weeks, pancreatic tissues from NOD mice fed insulin showed considerably less insulitis, and the residual MNC, although still largely CD4+ T cells plus macrophages, showed dense labeling for IL-4, IL-10, prostaglandin-E, and transforming growth factor-beta and an absence of IL-2, IFN-gamma or tumor necrosis factor-alpha Taken together with our previous findings, these data indicate that oral administration of insulin affects the development of diabetes in NOD mice through the generation of cells that elaborate immunoregulatory cytokines within the target organ and shift the balance from a Th1 to a Th2 pattern of cytokine expression.