Targeting the diverse immunological functions expressed by hepatic NKT cells.
Targeting the diverse immunological functions expressed by hepatic NKT cells.
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DOI：
10.1517/14728222.2011.584874
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发表时间：
2011-08
影响因子：
5.8
通讯作者：
Gregory SH
中科院分区：
文献类型：
--
作者：
Duwaerts CC;Gregory SH
NKT细胞约占小鼠肝淋巴细胞群的30%（人类约50%）。大多数小鼠肝NKT细胞[不变（i）NKT细胞]表达T细胞受体，由不变的Vα 14 J α18链组成。与传统的T细胞不同，iNKT细胞识别与MHC Ib类（CD 1d）分子相关的糖脂分子。据称，iNKT细胞在广泛的免疫事件中发挥关键作用;这种功能的确切性质通常不清楚。事实上，肝iNKT细胞活化的后果可能是有益的或有害的。α-半乳糖神经酰胺是iNKT细胞受体识别的原型糖脂，可刺激干扰素-γ和白细胞介素-4的快速产生。这些细胞因子表现出的相互抑制限制了α-半乳糖神经酰胺的潜在治疗价值。正在进行广泛的研究工作，以开发α-半乳糖神经酰胺类似物，其调节iNKT细胞活性并选择性地促进干扰素-γ或白细胞介素-4。本文综述了肝脏iNKT细胞及其在肝脏疾病中的作用。详细介绍了开发促进其有益贡献的治疗剂的努力。虽然越来越多的文献记载了α-GalCer类似物对IFN-γ和IL-4产生的不同作用，但这些类似物对其他iNKT细胞活性的作用，例如，细胞溶解和其他细胞因子的产生仍有待确定。类似地，在考虑这些类似物在临床试验中的效用之前，仍然需要对这些类似物在动物模型中对炎症和肝损伤的作用进行详尽的检查。
NKT cells comprise approximately 30% of the hepatic lymphoid population in mice (~50% in humans). Most mouse hepatic NKT cells [invariant (i)NKT cells] express T cell receptors, composed of invariant Vα14Jα18 chains. Unlike conventional T cells, iNKT cells recognize glycolipid molecules presented in association with MHC class Ib (CD1d) molecules. Purportedly, iNKT cells serve a key function in a wide range of immunological events; the precise nature of this function is often unclear. Indeed, the consequences of hepatic iNKT cell activation can be beneficial or detrimental. α-Galactosylceramide, the prototypic glycolipid recognized by the iNKT cell receptor, stimulates the rapid production of both interferon-γ and interleukin-4. The reciprocal suppression exhibited by these cytokines limits the potential therapeutic value of α-galactosylceramide. An extensive research effort is ongoing to develop α-galactosylceramide analogs that modulate iNKT cell activity and selectively promote interferon-γ or interleukin-4. This review provides a broad overview of hepatic iNKT cells and their purported role in liver disease. Efforts to develop therapeutic agents that promote their beneficial contributions are detailed. While a growing body of literature documents the differential effects of α-GalCer analogs on IFN-γ and IL-4 production, the effects of these analogs on other iNKT cell activities, e.g., cytolysis and the production of other cytokines, remain to be determined. Similarly, an exhaustive examination of the effects of these analogs on inflammation and liver injury in animal models remains prior to considering their utility in clinical trials.
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