von Herrath M G, Guerder S, Lewicki H, Flavell R A, Oldstone M B
Department of Neuropharmacology, Scripps Research Institute, La Jolla, California 92037, USA.
Immunity. 1995 Dec;3(6):727-38. doi: 10.1016/1074-7613(95)90062-4.
We evaluated the role of the costimulatory molecule B7-1 in overcoming peripheral ignorance in transgenic mice, which expressed the glycoprotein (GP) or nucleoprotein (NP) of lymphocytic choriomeningitis virus (LCMV) as the self-antigen in pancreatic beta cells. The viral transgenes or B7-1 alone did not induce autoimmune diabetes (IDDM). However, in bigenic mice expressing B7-1 and LCMV-GP, anti-self (viral) cytotoxic T lymphocytes (CTL) were activated without viral infection and spontaneous IDDM occurred. In contrast, bigenic RIP-B7-1 x RIP-NP mice with thymic expression of the self (viral-NP) antigen deleted the majority of their autoreactive CTL and did not develop spontaneous IDDM. However, these mice developed fast-onset IDDM 14 days after LCMV infection, whereas single-transgenic RIP-NP littermates developed IDDM only within 4-5 months. Rapid IDDM was associated with increased numbers of anti-self CTL and a predominance of IFN gamma produced by islet-infiltrating lymphocytes, whereas single transgenic RIP-NP littermates with slow-onset IDDM displayed less anti-self CTL and more IL-4- and IL-10-producing T lymphocytes in pancreatic infiltrates.
我们评估了共刺激分子B7-1在克服转基因小鼠外周免疫忽视中的作用，这些转基因小鼠在胰腺β细胞中表达淋巴细胞性脉络丛脑膜炎病毒（LCMV）的糖蛋白（GP）或核蛋白（NP）作为自身抗原。病毒转基因或单独的B7-1均未诱发自身免疫性糖尿病（IDDM）。然而，在表达B7-1和LCMV-GP的双转基因小鼠中，抗自身（病毒）细胞毒性T淋巴细胞（CTL）在没有病毒感染的情况下被激活，并且发生了自发性IDDM。相比之下，胸腺表达自身（病毒-NP）抗原的双转基因RIP-B7-1 x RIP-NP小鼠清除了大多数自身反应性CTL，并未发生自发性IDDM。然而，这些小鼠在LCMV感染后14天出现快速发作的IDDM，而单转基因RIP-NP同窝小鼠仅在4-5个月内发生IDDM。快速发作的IDDM与抗自身CTL数量增加以及胰岛浸润淋巴细胞产生的IFNγ占优势有关，而缓慢发作的IDDM的单转基因RIP-NP同窝小鼠在胰腺浸润中显示出较少的抗自身CTL以及更多产生IL-4和IL-10的T淋巴细胞。
