Spontaneous development of a pancreatic exocrine disease in CD28-deficient NOD mice
Spontaneous development of a pancreatic exocrine disease in CD28-deficient NOD mice
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DOI：
10.4049/jimmunol.180.12.7793
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发表时间：
2008-06-15
影响因子：
4.4
通讯作者：
Bluestone, Jeffrey A.
中科院分区：
文献类型：
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作者：
Meagher, Craig;Tang, Qizhi;Bluestone, Jeffrey A.
自身免疫性胰腺炎（AIP）是一种人类异质性自身免疫性疾病，其特征是外分泌胰腺进行性淋巴细胞和浆细胞浸润。在这项研究中，我们报道了调节性T细胞缺陷NOD。CD28KO小鼠会自发产生与人类疾病非常相似的AIP。NOD小鼠AIP与外分泌胰腺CD4(+) T细胞、CD8(+) T细胞和B细胞引起的严重管周和实质炎症有关。脾CD4(+) T细胞是AIP发生的必要条件和充分条件。来自受感染小鼠的自身抗体和自身反应性T细胞识别出一种类似于50 kda的蛋白质，被鉴定为胰腺淀粉酶。重要的是，耐受性淀粉酶偶联的固定脾细胞显著改善了疾病的严重程度，这表明该蛋白作为一种关键的自身抗原起作用。在调节性T细胞缺陷NOD中这种自发性胰腺淀粉酶特异性AIP的建立和表征。CD28KO小鼠为研究人类自身免疫性胰腺炎的发病机制和开发新的治疗方法提供了一个很好的模型。
Autoimmune pancreatitis (AIP) is a heterogeneous autoimmune disease in humans characterized by a progressive lymphocytic and plasmacytic infiltrate in the exocrine pancreas. In this study, we report that regulatory T cell-deficient NOD.CD28KO mice spontaneously develop AIP that closely resembles the human disease. NOD mouse AIP was associated with severe periductal and parenchymal inflammation of the exocrine pancreas by CD4(+) T cells, CD8(+) T cells, and B cells. Spleen CD4(+) T cells were found to be both necessary and sufficient for the development of AIP. Autoantibodies and autoreactive T cells from affected mice recognized a similar to 50-kDa protein identified as pancreatic amylase. Importantly, administration of tolerogenic amylase-coupled fixed spleen cells significantly ameliorated disease severity, suggesting that this protein functions as a key autoantigen. The establishment and characterization of this spontaneous pancreatic amylase-specific AIP in regulatory T cell-deficient NOD.CD28KO mice provides an excellent model for the study of disease pathogenesis and development of new therapies for human autoimmune pancreatitis.