Efficacy of clonal deletion vs. anergy of self-reactive CD4 T-cells for the prevention and reversal of autoimmune diabetes.
Efficacy of clonal deletion vs. anergy of self-reactive CD4 T-cells for the prevention and reversal of autoimmune diabetes.
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克隆缺失与自身反应性 CD4 T 细胞无反应对于预防和逆转自身免疫性糖尿病的功效。
DOI：
10.1016/j.jaut.2005.04.003
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发表时间：
2005
期刊：
影响因子：
--
通讯作者：
Brumeanu,Teodor-D
中科院分区：
文献类型：
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作者：
Preda-Pais,Anca;Stan,AlexandruC;Casares,Sofia;Bona,Constantin;Brumeanu,Teodor-D
自身反应性CD4 t细胞在触发和维持器官特异性自身免疫性疾病中发挥重要作用。沉默或消除这些细胞可以预防和逆转自身免疫过程。我们之前的研究表明，在双转基因小鼠中单剂量给予可溶性二聚体MHC ii肽嵌合体（DEF）可以延缓自身免疫性糖尿病的发作，并在已经患有糖尿病的小鼠中恢复正常血糖，持续1周。DEF二聚体的保护作用依赖于诱导脾脏中糖尿病性CD4 T细胞的能量，以及刺激胰腺中分泌il -10的T调节性1型细胞。在此，我们表明，通过克隆删除胸腺和外周区室中的糖尿病源性CD4 t细胞，八聚体形式的DEF使疾病的保护和逆转时间延长了一倍。缺失发生在激活诱导的细胞死亡之后，再分配和质膜脂筏中FAS-FADD凋亡模块的信号传导。我们之前和现在的数据表明，首先，DEF价态转化为对抗原特异性CD4 t细胞的各种影响，即Th2免疫偏差、能量和凋亡。其次，目前的研究结果表明克隆缺失比激活糖尿病源性CD4 t细胞在保护和逆转自身免疫性糖尿病方面具有更好的功效。
The self-reactive CD4 T-cells play an essential role in triggering and sustaining organ-specific autoimmune diseases. Silencing or elimination of these cells can prevent and reverse an autoimmune process. We have previously showed that a single dose-administration of a soluble dimeric MHC II–peptide chimera (DEF) in double-transgenic mice delayed the onset autoimmune diabetes, and restored the euglycemia in already diabetic mice for a period of 1 week. DEF dimer protection relied on induction of anergy of diabetogenic CD4 T-cells in spleen, and stimulation of IL-10-secreting T regulatory type 1 cells in pancreas. Herein, we show that an octameric form of DEF has doubled the period of protection and reversal of disease by clonal deletion of diabetogenic CD4 T-cells in both the thymic and peripheral compartments. Deletion occurred by activation-induced cell death subsequent to repartitioning and signaling of FAS–FADD apoptotic module in the plasma membrane lipid rafts. Our previous and present data indicated first, that DEF valence translates into various effects on the antigen-specific CD4 T-cells, i.e., Th2 immune deviation, anergy, and apoptosis. Second, the present findings argue for a better efficacy of clonal deletion than anergy of diabetogenic CD4 T-cells for the protection and reversal of autoimmune diabetes.