Polyarginine-mediated protein delivery to dendritic cells presents antigen more efficiently onto MHC class I and class II and elicits superior antitumor immunity
Polyarginine-mediated protein delivery to dendritic cells presents antigen more efficiently onto MHC class I and class II and elicits superior antitumor immunity
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DOI：
10.1038/sj.jid.5700335
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发表时间：
2006-08-01
影响因子：
6.5
通讯作者：
Shimada, Shinji
中科院分区：
文献类型：
--
作者：
Mitsui, Hiroshi;Inozume, Takashi;Shimada, Shinji
蛋白质转导结构域(PTD)已越来越多地被用来在体外和体内向各种类型的细胞输送试剂。我们先前已经证明，HIV TAT-PTD全蛋白抗原(AGS)转导的树突状细胞(DC)刺激抗原特异性CD8(+)和CD4(+)T细胞。尽管产生的细胞毒性T淋巴细胞(CTL)活性足以阻止荷有抗原表达肿瘤的小鼠的种植，但TAT-PTD抗原转导的DC治疗荷瘤小鼠导致了一些动物的肿瘤消退。最近，其他几个PTD被报道促进比TAT-PTD更高的转导效率。为了在肿瘤疫苗研究中评估单个PTD在诱导免疫反应中的作用，我们设计了包含三个不同PTD的重组融合卵清蛋白(OVA)，其中包括已知的最有效的PTD(聚精氨酸(R9)-PTD)。我们的结果表明，含有R9-PTD的OVA最有效地转导DC，并且转导效率与体内和体外抗原特异性的CD4(+)和CD8(+)T细胞的激活程度密切相关。R9-PTD-OVA转导的树突状细胞在荷瘤(OVA表达)小鼠体内反复免疫可增强抗肿瘤免疫功能，并与佐剂联合注射可引起肿瘤的完全排斥反应。这种疫苗接种策略可能在临床上适用，并为目前正在使用的疫苗提供理论和实践上的优势。
Protein transduction domains (PTDs) have been used increasingly to deliver reagents to a variety of cell types in vitro and in vivo. We have previously shown that HIV TAT-PTD-containing whole protein antigens (Ags)transduced dendritic cells (DCs) stimulated Ag-specific CD8(+) and CD4(+) T cells. Although the cytotoxic T lymphocytes (CTL) activity generated was sufficient to prevent engraftment of mice with Ag-expressing tumors, treatment of tumor-bearing mice with TAT-PTD Ag-transduced DCs resulted in tumor regression in some animals. Recently, several other PTDs were reported to promote higher transduction efficiencies than TAT-PTD. To evaluate the role of individual PTDs in induction of immune responses in tumor vaccination studies, we engineered recombinant fusion Ovalbumin (OVA) that contained three differrent PTDs, including the most efficacious known PTD (polyarginine (R9)- PTD). Our results demonstrated that R9-PTD-containing OVA transduced DCs most efficiently, and that transduction efficacy was closely correlated with the extent of Ag-specific CD4(+) and CD8(+) T-cell activation in vitro and in vivo. Repeated vaccination with R9-PTD-OVA-transduced DC in (OVA-expressing) tumor-bearing mice induced enhanced antitumor immunity, and elicited complete rejection of tumors when DC was co-injected with adjuvants. This vaccination strategy may be clinically applicable, and offers theoretical and practical advantages to those that are in current use.