Dahlén E, Dawe K, Ohlsson L, Hedlund G
Pharmacia & Upjohn, Lund Research Center, Sweden.
J Immunol. 1998 Apr 1;160(7):3585-93.
The nonobese diabetic (NOD) mouse spontaneously develops autoimmune insulin-dependent diabetes mellitus (IDDM) and serves as an animal model for human type I diabetes. TNF-alpha is known to be produced by islet-infiltrating mononuclear cells during insulitis and subsequent beta cell destruction and has been implicated in the pathogenesis of IDDM. Previously, T cells have been suggested as the main source of TNF-alpha in the islet infiltrate. However, on immunohistochemical analysis of TNF-alpha expression in islets, we are able to show that the staining pattern of TNF-alpha resembles that of dendritic cells (DC) and macrophages (Mphi) rather than T cells and that TNF-alpha is expressed in islets at the very early stages of insulitis when no T cells are detected. On double staining for TNF-alpha and cell surface markers, we can demonstrate that TNF-alpha staining clearly correlates with DC and Mphi, whereas there is a poor correlation with T cells. This feature was observed at both early and late stages of insulitis. TNF-alpha expression was also seen in NOD-SCID islets, in addition to a peri-islet infiltration consisting of DC and Mphi, indicating that T cells are not required for the early DC and Mphi infiltration and TNF-alpha expression in islets. In conclusion, our results show that DC and Mphi are the major, early source of TNF-alpha in the NOD islet infiltrate and that TNF-alpha can be expressed independently of T cells, indicating that the early DC and Mphi infiltration and expression of TNF-alpha are crucial in initiation of diabetes.
非肥胖型糖尿病（NOD）小鼠会自发发展为自身免疫性胰岛素依赖型糖尿病（IDDM），可作为人类I型糖尿病的动物模型。已知在胰岛炎及随后的β细胞破坏过程中，胰岛浸润的单核细胞会产生肿瘤坏死因子-α（TNF-α），且其与IDDM的发病机制有关。此前，T细胞被认为是胰岛浸润中TNF-α的主要来源。然而，通过对胰岛中TNF-α表达的免疫组织化学分析，我们发现TNF-α的染色模式类似于树突状细胞（DC）和巨噬细胞（Mphi），而非T细胞，并且在胰岛炎的早期阶段，当未检测到T细胞时，胰岛中就有TNF-α表达。对TNF-α和细胞表面标志物进行双重染色时，我们发现TNF-α染色与DC和Mphi明显相关，而与T细胞的相关性较差。在胰岛炎的早期和晚期均观察到这一特征。在NOD-SCID小鼠的胰岛中也观察到了TNF-α的表达，此外还有由DC和Mphi组成的胰岛周围浸润，这表明胰岛早期的DC和Mphi浸润及TNF-α表达并不需要T细胞。总之，我们的结果表明，DC和Mphi是NOD胰岛浸润中TNF-α的主要早期来源，且TNF-α可独立于T细胞表达，这表明早期的DC和Mphi浸润及TNF-α表达在糖尿病的发病起始过程中至关重要。
