Tumor immunotherapy using bone marrow-derived dendritic cells overexpressing Toll-like receptor adaptors
Tumor immunotherapy using bone marrow-derived dendritic cells overexpressing Toll-like receptor adaptors
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DOI：
10.1016/j.febslet.2007.06.019
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发表时间：
2007-07-24
期刊：
影响因子：
3.5
通讯作者：
Seya, Tsukasa
中科院分区：
文献类型：
--
作者：
Akazawa, Takashi;Shingai, Masashi;Seya, Tsukasa
髓样树突状细胞（mDC）在启动针对癌症和感染性疾病的免疫应答中起重要作用。在mDC上表达的Toll样受体（TLR）识别微生物产物以引发mDC成熟的信号，包括细胞因子产生、抗原呈递和效应细胞的诱导。TLR激动剂作为佐剂调节mDC的功能。在TLR信号传导中，MyD 88和TRIF/TICAM-1是主要的TLR衔接分子，其在过表达时能够在没有TLR刺激的情况下阻断下游信号。我们使用慢病毒载体成功地将衔接子导入小鼠骨髓来源的mDC中。在体外将MyD 88引入mDC中导致IL-6和IL-12 p40的产生，而TICAM-1的引入刺激干扰素（IFN）-α的产生。mDC中TICAM-1而非MyD 88的表达轻微诱导了共刺激分子CD 86，而在对其他TLR刺激的响应中观察到CD 86的显著上调。MyD 88和TICAM-1均增强同种异体混合淋巴细胞反应（MLR）。当与表达MyD 88或TICAM-1的mDC孵育时，预暴露于肿瘤抗原的离体小鼠脾细胞表现出抗肿瘤细胞毒性。使用mDC过继转移和同基因小鼠肿瘤植入模型，我们建立了一种抗肿瘤免疫疗法，其中肿瘤生长被衔接子操纵的mDC阻滞。(c)2007年欧洲生物化学学会联合会。Elsevier B. V.出版，保留所有权利。
Myeloid dendritic cells (mDCs) play an important role in the initiation of immune responses to cancer and infectious diseases. Toll-like receptors (TLRs) expressed on mDCs recognize microbial products to elicit signals for mDC maturation, including cytokine production, antigen-presentation and induction of effector cells. TLR agonists work as adjuvants to modulate the function of mDCs. In TLR signaling, MyD88 and TRIF/TICAM-1 are major TLR adaptor molecules, which when overexpressed are able to transduce downstream signals without TLR stimuli. We successfully introduced the adaptors into mouse bone marrowderived mDCs using lentiviral vectors. Introduction of MyD88 into mDCs in vitro led to the production of IL-6 and IL-12p40 while introduction of TICAM-1 stimulated interferon (IFN)-alpha production. Expression of TICAM-1, but not MyD88, in mDCs slightly induced the co-stimulatory molecule CD86, while significant upregulation of CD86 was observed in response to other TLR stimuli. Both MyD88 and TICAM-1 augmented allogeneic mixed lymphocyte reaction (MLR). Ex vivo mouse spleen cells pre-exposed to tumor antigen exhibited antitumor cytotoxicity when incubated with MyD88- or TICAM-1 -expressing mDCs. Using mDC adoptive transfer and a syngeneic mouse tumor implant model, we established an antitumor immunotherapy whereby tumor growth is retarded by adaptor-manipulated mDCs. (c) 2007 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.