Endotoxin-Induced Myeloid-Derived Suppressor Cells Inhibit Alloimmune Responses via Heme Oxygenase-1
Endotoxin-Induced Myeloid-Derived Suppressor Cells Inhibit Alloimmune Responses via Heme Oxygenase-1
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DOI：
10.1111/j.1600-6143.2009.02757.x
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发表时间：
2009-09-01
影响因子：
8.8
通讯作者：
Le Moine, A.
中科院分区：
文献类型：
--
作者：
De Wilde, V.;Van Rompaey, N.;Le Moine, A.
炎症和癌症与共表达CD11b和GR-1抗原的髓系抑制细胞(MDSCs)异质性群体的T细胞反应障碍有关。近年来，MDSCs参与了共刺激阻断诱导的大鼠移植耐受，这种耐受受诱导型一氧化氮合酶(INOS)的调控。在这里，我们描述了CD11b+GR-1+MDSC相容的细胞在重复注射脂多糖(LPS)后出现的一种独特的抑制机制。在混合淋巴细胞反应和多克隆刺激试验中，这些细胞均抑制T细胞的增殖和Th1、Th2细胞因子的产生。在未经治疗的受者中，转移来自脂多糖处理的小鼠的CD11b+细胞显著延长了同种异体皮肤移植的存活时间。它们产生大量的IL-10，并表达血红素加氧酶-1(HO-1)，这是一种应激反应酶，具有免疫调节和细胞保护特性，以前与MDSC的活性不相关。特异性抑制剂SnPP对HO-1的抑制作用可完全消除T细胞抑制和IL-10的产生。相反，iNOS和精氨酸酶1的抑制都不影响抑制作用。重要的是，在CD11b+细胞转移之前抑制HO-1可以阻止同种异体排斥反应的延迟，揭示了与移植相关的MDSC相关的新的抑制机制。
Inflammation and cancer are associated with impairment of T-cell responses by a heterogeneous population of myeloid-derived suppressor cells (MDSCs) coexpressing CD11b and GR-1 antigens. MDSCs have been recently implicated in costimulation blockade-induced transplantation tolerance in rats, which was under the control of inducible NO synthase (iNOS). Herein, we describe CD11b+GR-1+MDSC-compatible cells appearing after repetitive injections of lipopolysaccharide (LPS) using a unique mechanism of suppression. These cells suppressed T-cell proliferation and Th1 and Th2 cytokine production in both mixed lymphocyte reaction and polyclonal stimulation assays. Transfer of CD11b+ cells from LPS-treated mice in untreated recipients significantly prolonged skin allograft survival. They produced large amounts of IL-10 and expressed heme oxygenase-1 (HO-1), a stress-responsive enzyme endowed with immunoregulatory and cytoprotective properties not previously associated with MDSC activity. HO-1 inhibition by the specific inhibitor, SnPP, completely abolished T-cell suppression and IL-10 production. In contrast, neither iNOS nor arginase 1 inhibition did affect suppression. Importantly, HO-1 inhibition before CD11b+ cell transfer prevented the delay of allograft rejection revealing a new MDSC-associated suppressor mechanism relevant for transplantation.