Dendritic cells induce autoimmune diabetes and maintain disease via de novo formation of local lymphoid tissue.
Dendritic cells induce autoimmune diabetes and maintain disease via de novo formation of local lymphoid tissue.
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DOI：
10.1084/jem.188.8.1493
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发表时间：
1998-10-19
期刊：
影响因子：
--
通讯作者：
Zinkernagel RM
中科院分区：
文献类型：
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作者：
Ludewig B;Odermatt B;Landmann S;Hengartner H;Zinkernagel RM
自身反应性T细胞的活化可导致自身免疫性疾病，例如胰岛素依赖型糖尿病（IDDM）。在大鼠胰岛素启动子控制下表达淋巴细胞性脉络丛脑膜炎病毒糖蛋白（LCMV-GP）的转基因小鼠（RIP-GP小鼠）中，研究了最有效的专职抗原呈递细胞树突状细胞（DC）对IDDM的启动和维持。我们表明，过继转移DC组成性表达免疫显性细胞毒性T淋巴细胞（CTL）表位的LCMV-GP，RIP-GP小鼠发展自身免疫性糖尿病。DC激活的CTL的动力学和功能研究表明，IDDM的发展依赖于抗原刺激的剂量和时间。引人注目的是，DC的重复CTL激活导致胰岛的严重破坏性单核细胞浸润，但也导致胰腺实质中胰岛相关的有组织淋巴样结构的从头形成。此外，重复DC免疫诱导IDDM与淋巴新生也在穿孔素缺陷RIP-GP小鼠，说明CD8 + T细胞依赖性炎症机制独立于穿孔素可以诱导IDDM。因此，DC呈递自身抗原不仅是自身反应性T细胞的有效诱导剂，而且还有助于局部维持外周免疫应答;因此，针对先前被忽视的自身抗原的自身免疫的诱导代表了潜在的危害，特别是在基于DC的抗肿瘤治疗中。
Activation of autoreactive T cells can lead to autoimmune diseases such as insulin-dependent diabetes mellitus (IDDM). The initiation and maintenance of IDDM by dendritic cells (DC), the most potent professional antigen-presenting cells, were investigated in transgenic mice expressing the lymphocytic choriomeningitis virus glycoprotein (LCMV-GP) under the control of the rat insulin promoter (RIP-GP mice). We show that after adoptive transfer of DC constitutively expressing the immunodominant cytotoxic T lymphocyte (CTL) epitope of the LCMV-GP, RIP-GP mice developed autoimmune diabetes. Kinetic and functional studies of DC-activated CTL revealed that development of IDDM was dependent on dose and timing of antigenic stimulation. Strikingly, repeated CTL activation by DC led to severe destructive mononuclear infiltration of the pancreatic islets but also to de novo formation of islet-associated organized lymphoid structures in the pancreatic parenchyma. In addition, repetitive DC immunization induced IDDM with lymphoid neogenesis also in perforin-deficient RIP-GP mice, illustrating that CD8+ T cell–dependent inflammatory mechanisms independent of perforin could induce IDDM. Thus, DC presenting self-antigens not only are potent inducers of autoreactive T cells, but also help to maintain a peripheral immune response locally; therefore, the induction of autoimmunity against previously ignored autoantigens represents a potential hazard, particularly in DC-based antitumor therapies.