Delayed type hypersensitivity-induced myeloid-derived suppressor cells regulate autoreactive T cells
Delayed type hypersensitivity-induced myeloid-derived suppressor cells regulate autoreactive T cells
复制标题
DOI：
10.1002/eji.201141696
复制
发表时间：
2011-10-01
影响因子：
5.4
通讯作者：
Zoeller, Margot
中科院分区：
文献类型：
--
作者：
Singh, Vibhuti;Mueller, Ulrike;Zoeller, Margot
目前迫切需要对自身免疫性疾病进行温和而有效的治疗。一种这样的治疗方法，长期维持慢性延迟型超敏反应，已被描述为斑秃（AA），一种影响毛囊的自身免疫性疾病。治疗效果的分子机制尚不清楚，但可能与髓源性抑制细胞（MDSCs）有关。aa感染小鼠用方酸二丁基酯（SADBE）治疗。分析了sadebe处理的AA淋巴细胞和sadebe诱导的MDSCs共培养的AA淋巴细胞的免疫反应性。全转视黄酸破坏了SADBE的疗效，这促使MDSCs分化，证实了MDSCs在治疗性SADBE治疗中的核心作用。SADBE和SADBE诱导的MDSCs对AA皮肤裂解液（自身抗原）的持续自身反应性t细胞增殖有强烈的干扰，这伴随着弱的ζ链下调和Lck激活的强烈受损。相反，sadbe诱导的MDSCs激活线粒体凋亡通路和阻断抗凋亡PI3K/Akt通路不需要t细胞受体参与。凋亡诱导与sadbe诱导的MDSCs中tnf - α高表达和AA淋巴细胞中TNFRI水平升高相关。sadbe诱导的MDSCs干扰持续的自身反应性T细胞增殖并促进这些T细胞凋亡，这使得由慢性延迟型超敏反应诱导和维持的MDSCs成为器官相关自身免疫性疾病的有希望的治疗方法。
Mild but efficient treatments of autoimmune diseases are urgently required. One such therapy, long-term maintenance of chronic delayed type hypersensitivity, has been described for alopecia areata (AA), a hair follicle-affecting autoimmune disease. The molecular mechanisms underlying the therapeutic efficacy are unknown, but may involve myeloid-derived suppressor cells (MDSCs). AA-affected mice were treated with squaric acid dibutyl ester (SADBE). The immunoreactivity of SADBE-treated AA lymphocytes and of AA lymphocytes co-cultured with SADBE-induced MDSCs was analyzed. The curative effect of SADBE was abolished by all-transretinoic acid, which drives MDSCs into differentiation, confirming a central role for MDSCs in therapeutic SADBE treatment. SADBE and SADBE-induced MDSCs strongly interfered with sustained autoreactive T-cell proliferation in response to AA skin lysate (autoantigen), which was accompanied by weak zeta-chain down-regulation and strongly impaired Lck activation. In contrast, activation of the mitochondrial apoptosis pathway and blockade of the anti-apoptotic PI3K/Akt pathway by SADBE-induced MDSCs did not require T-cell receptor engagement. Apoptosis induction correlated with high TNF-alpha expression in SADBE-induced MDSCs and elevated TNFRI levels in AA lymphocytes. SADBE-induced MDSCs interfere with persisting autoreactive T-cell proliferation and promote apoptosis of these T cells, which qualifies MDSCs induced and maintained by chronic delayed type hypersensitivity reactions as promising therapeutics in organ-related autoimmune diseases.