Molecular mechanisms of T-cell receptor and costimulatory molecule ligation/blockade in autoimmune disease therapy.
Molecular mechanisms of T-cell receptor and costimulatory molecule ligation/blockade in autoimmune disease therapy.
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DOI：
10.1111/j.1600-065x.2009.00773.x
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发表时间：
2009-05
影响因子：
8.7
通讯作者：
Miller SD
中科院分区：
文献类型：
--
作者：
Podojil JR;Miller SD
促炎性CD 4 + T细胞介导的自身免疫性疾病，如多发性硬化症和1型糖尿病，被假设是由活化的抗原呈递细胞（APC）将自身抗原呈递给自身反应性干扰素-γ（IFN-γ）和白细胞介素-17（IL-17）产生的CD 4 + Th 1/17细胞引发和维持的。迄今为止，大多数FDA批准的自身免疫性疾病疗法主要集中在免疫炎症活动的全面抑制上。该领域正在进行的研究的目标是开发抑制/消除活化的自身反应性细胞的疗法以及允许直接阻断自身反应性免疫细胞功能的有害作用的抗原特异性治疗。根据双信号假说，初始抗原特异性CD 4 + T细胞的激活需要刺激T细胞受体（TCR）（信号1）和刺激共刺激分子（信号2）。在促炎和抗炎免疫细胞活性之间也存在平衡，这受到激活信号的类型和强度以及初始CD 4 + T细胞被激活的局部细胞因子环境的调节。为此，大多数正在进行的研究集中在不存在共刺激分子刺激或刺激辅助分子的潜在阻断的情况下递送次优TCR刺激。因此，参与诱导CD 4 + T细胞无反应性的信号传导途径，与活化相反，是人们非常感兴趣的话题。
Pro-inflammatory CD4+ T cell mediated autoimmune diseases, such as multiple sclerosis and type 1 diabetes, are hypothesized to be initiated and maintained by activated antigen presenting cells (APCs) presenting self-antigen to self-reactive interferon-gamma (IFN-γ) and interleukin-17 (IL-17) producing CD4+ Th1/17 cells. To date, the majority of FDA approved therapies for autoimmune disease primarily focus on the global inhibition of immune inflammatory activity. The goal of ongoing research in this field is to develop both therapies that inhibit/eliminate activated autoreactive cells as well as antigen-specific treatments which allow for the directed blockade of the deleterious effects of self-reactive immune cell function. According to the two-signal hypothesis, activation of a naïve antigen-specific CD4+ T cell requires both stimulation of the T cell receptor (TCR) (signal 1), and stimulation of costimulatory molecules (signal 2). There also exists a balance between pro-inflammatory and anti-inflammatory immune cell activity, which is regulated by the type and strength of the activating signal as well as the local cytokine milieu in which the naïve CD4+ T cell is activated. To this end, the majority of ongoing research is focused on the delivery of suboptimal TCR stimulation in the absence of costimulatory molecule stimulation, or potential blockade of stimulatory accessory molecules. Therefore, the signaling pathways involved in the induction of CD4+ T cell anergy, as apposed to activation, are topics of intense interest.