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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Unusual resistance of ALR/Lt mouse β cells to autoimmune destruction: Role for β cell- expressed resistance determinants
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Unusual resistance of ALR/Lt mouse β cells to autoimmune destruction: Role for β cell- expressed resistance determinants

机译：ALR / Lt小鼠β细胞对自身免疫破坏的异常抗性：β细胞表达的抗性决定簇的作用

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摘要

Genetic analysis of autoimmune insulin-dependent diabetes mel- litus (IDDM) has focused on genes controlling immune functions, with little investigation of innate susceptibility determinants ex- pressed at the level of target p cells. The Alloxan (AL) Resistant (R) Leiter (Lt) mouse strain, closely related to the IDDM-prone nono- bese diabetic (NOD)/Lt strain, demonstrates the importance of such determinants. ALR mice are unusual in their high constitutive expression of molecules associated with dissipation of free-radical stress systemically and at the β-cell level. ALR islets were found to be remarkably resistant to two different combinations of β- cytotoxic cytokines (IL-1β, tumor necrosis factor α. and IFN-γ) that destroyed islets from the related NOD and alloxan-susceptible strains. The close MHC relatedness between the NOD and ALR strains (H2-K~d and H2-A~g7 identical) allowed us to examine whether ALR islet cells could survive autoimmune destruction by NOD-derived K~d-restricted diabetogenic cytotoxic T lymphocyte clones (Al4 and the insulin-reactive G9C8 clones). Both clones killed islet cells from all K~d-expressing strains except ALR. ALR resistance to diabetogenic immune systems was determined in vivo by means of adoptive transfer of the G9C8 clone or by chimerizing lethally irradiated ALR or reciprocal (ALR x NOD)F_1 recipients with NOD hone marrow. In all in vivo systems, ALR and F_1 female recipients of NOD marrow remained IDDM free: in contrast, all of the NOD recipients became diabetic. In conclusion, the ALR mouse presents a unique opportunity to identify dominant IDDM resistance deter- minants expressed at the β cell level.
机译：自身免疫性胰岛素依赖型糖尿病患者（IDDM）的基因分析集中于控制免疫功能的基因，很少研究在靶p细胞水平表达的先天易感性决定因素。与易发生IDDM的诺贝司糖尿病（NOD）/ Lt菌株密切相关的抗四氧嘧啶（AL）的莱特（Lt）小鼠品系证明了此类决定因素的重要性。 ALR小鼠的分子高组成型表达与系统性地以及在β细胞水平上消除自由基应力有关的分子不同。发现ALR胰岛对两种不同的β细胞毒性细胞因子组合（IL-1β，肿瘤坏死因子α和IFN-γ）具有明显的抗性，这些组合破坏了相关NOD和四氧嘧啶敏感性菌株的胰岛。 NOD和ALR菌株之间的紧密MHC相关性（H2-K〜d和H2-A〜g7相同）使我们能够检查ALR胰岛细胞能否在NOD衍生的K〜d限制性糖尿病致细胞毒性T淋巴细胞克隆的自体免疫破坏中幸存（Al4和胰岛素反应性G9C8克隆）。除ALR外，两个克隆均杀死了所有表达Kdd的菌株的胰岛细胞。在体内通过过继转移G9C8克隆或通过用NOD骨髓嵌合致死性照射的ALR或倒数（ALR x NOD）F_1受体来确定ALR对糖尿病免疫系统的抵抗力。在所有体内系统中，NOD骨髓的ALR和F_1雌性受体仍然不含IDDM：相反，所有NOD受体都患有糖尿病。总之，ALR小鼠提供了独特的机会来鉴定以β细胞水平表达的主要IDDM抗性决定子。

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