Improved outcomes in NOD mice treated with a novel Th2 cytokine-biasing NKT cell activator
Improved outcomes in NOD mice treated with a novel Th2 cytokine-biasing NKT cell activator
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DOI：
10.4049/jimmunol.178.3.1415
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发表时间：
2007-02-01
影响因子：
4.4
通讯作者：
Porcelli, Steven A.
中科院分区：
文献类型：
--
作者：
Forestier, Claire;Takaki, Toshiyuki;Porcelli, Steven A.
α-半乳糖神经酰胺（α-GalCer）激活CD 1d限制性不变NKT（iNKT）细胞可显著抑制NOD小鼠糖尿病的发生。这种保护作用的机制是复杂的，涉及Th 1和Th 2细胞因子以及包括致耐受性树突状细胞在内的调节细胞网络。在当前的研究中，我们评估了一种新描述的合成的aGalCer类似物（C20：2），其激发Th 2偏向的细胞因子应答，以评估其对NOD小鼠中的疾病进展和免疫病理学的影响。用α GalCer C20：2治疗NOD小鼠显著延迟并降低了糖尿病的发病率。这与显著抑制胰岛炎的晚期进展、减少自身反应性CD 8（+）T细胞对胰岛的浸润以及预防胰腺引流淋巴结中不同树突状细胞亚群相对比例的疾病进展相关变化有关。用aGalCer C20：2观察到的多种有利效果比与刺激Th 1和Th 2细胞因子分泌的更混合模式的密切相关的aGalCer类似物直接比较中观察到的效果显著更显著。与先前报道的Th 2-偏斜鼠iNKT细胞激动剂不同，aGalCer C20：2类似物对人iNKT细胞具有强烈刺激性，因此值得进一步研究作为人类疾病的潜在免疫调节剂。
Activation of CD1d-restricted invariant NKT (iNKT) cells by a-galactosylceramide (alpha GalCer) significantly suppresses development of diabetes in NOD mice. The mechanisms of this protective effect are complex, involving both Th1 and Th2 cytokines and a network of regulatory cells including tolerogenic dendritic cells. In the current study, we evaluated a newly described synthetic aGalCer analog (C20:2) that elicits a Th2-biased cytokine response for its impact on disease progression and immunopathology in NOD mice. Treatment of NOD mice with alpha GalCer C20:2 significantly delayed and reduced the incidence of diabetes. This was associated with significant suppression of the late progression of insulitis, reduced infiltration of islets by autoreactive CD8(+) T cells, and prevention of progressive disease-related changes in relative proportions of different subsets of dendritic cells in the draining pancreatic lymph nodes. Multiple favorable effects observed with aGalCer C20:2 were significantly more pronounced than those seen in direct comparisons with a closely related analog of aGalCer that stimulated a more mixed pattern of Th1 and Th2 cytokine secretion. Unlike a previously reported Th2-skewing murine iNKT cell agonist, the aGalCer C20:2 analog was strongly stimulatory for human iNKT cells and thus warrants further examination as a potential immunomodulatory agent for human disease.