Targeting T cell-specific costimulators and growth factors in a model of autoimmune hemolytic anemia
Targeting T cell-specific costimulators and growth factors in a model of autoimmune hemolytic anemia
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DOI：
10.4049/jimmunol.179.5.2844
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发表时间：
2007-09-01
影响因子：
4.4
通讯作者：
Abbas, Abul K.
中科院分区：
文献类型：
--
作者：
Hoyer, Katrina K.;Wolslegel, Kristen;Abbas, Abul K.
尽管已证实调节机制的失败是许多自身免疫性疾病的基础，但激活自身反应性淋巴细胞的刺激因素仍然知之甚少。定义这些刺激将导致自身免疫性疾病的治疗策略。由于调节性T细胞的缺乏，IL-2基因缺陷的小鼠发生了自发的自身免疫，在BALB/c的背景下，它们很快就死于自身免疫性溶血性贫血。为了确定共刺激通路在这种自身免疫性疾病的不同组成部分中的重要性，我们首先将IL-2缺陷小鼠与缺乏CD28或CD40L的小鼠杂交。CD28的消除减少了自身反应性T细胞的激活和淋巴增殖以及自身抗体的产生，而CD40L的消除减少了自身抗体的产生，而不影响T细胞的扩增和积聚。为了研究IL-7的作用，我们用中和抗体阻断了IL-7R信号。这种治疗方法抑制了自身抗体的产生和自身免疫性溶血性贫血的发展。总之，这些数据表明，特定的共刺激信号和细胞因子信号在IL-2缺陷小鼠的自发自身抗体介导的疾病中起着关键作用。
Although it is established that failure of regulatory mechanisms underlies many autoimmune diseases, the stimuli that activate autoreactive lymphocytes remain poorly understood. Defining these stimuli will lead to therapeutic strategies for autoimmune diseases. IL-2-deficient mice develop spontaneous autoimmunity, because of a deficiency of regulatory T cells, and on the BALB/c background, they rapidly die from autoimmune hemolytic anemia. To define the importance of costimulatory pathways in various components of this autoimmune disorder, we first intercrossed IL-2-deficient mice with mice lacking CD28 or CD40L. Elimination of CD28 reduced the activation of autoreactive T cells and lymphoproliferation as well as production of autoantibodies, whereas elimination of CD40L reduced autoantibody production without affecting T cell expansion and accumulation. To examine the role of IL-7, we blocked IL-7R signaling with neutralizing Abs. This treatment inhibited the production of autoantibodies and the development of autoimmune hemolytic anemia. Together, these data indicate that specific costimulatory and cytokine signals are critical for the spontaneous autoantibody-mediated disease that develops in IL-2-deficient mice.