Dendritic Cells Transduced with Protein Antigens Induce Cytotoxic Lymphocytes and Elicit Antitumor Immunity1
Dendritic Cells Transduced with Protein Antigens Induce Cytotoxic Lymphocytes and Elicit Antitumor Immunity1
复制标题
用蛋白质抗原转导的树突状细胞诱导细胞毒性淋巴细胞并引发抗肿瘤免疫1
作者：
N. Shibagaki;M. Udey
正在开发基于树突状细胞（DC）的疫苗用于治疗癌症患者，部分原因是DC是CD 8 + CTL的有效诱导剂。DC MHC I类：CTL诱导所需的抗原肽复合物通常通过将DC与肽一起孵育或通过用编码蛋白Ag的cDNA（或病毒载体）转染（或转导）DC来产生。前一种方法是可行的，当MHC I类抗原和相关肽已知。后一种方法可能受到低效DC转染（转导）和/或与病毒载体的制备和使用相关的困难的阻碍。在此，我们证明，一个细菌重组模型肿瘤相关的银（OVA），其中包含的HIV达特蛋白转导结构域（PTD）容易工程化和纯化，有效地转导小鼠淋巴细胞和DC，并通过蛋白酶体处理的MHC I类限制性呈递给CTL。此外，含有PTD的rOVA与天然OVA或缺乏PTD的rOVA一样有效地被DC加工并呈递给CD 4 T细胞。PTD-OVA转导的DC以Th细胞非依赖性方式在体内诱导CTL，并针对表达OVA的肿瘤接种疫苗。相反，缺乏PTD的rOVA不进入DC MHC I类呈递途径，并且用该蛋白质处理的DC在体内不引发OVA特异性CTL。用PTD-OVA转导的DC治疗具有临床上明显的OVA表达肿瘤的小鼠导致一些动物的肿瘤消退。这种简单的疫苗接种策略可能会转化为癌症和其他严重疾病患者的DC治疗。
Dendritic cell (DC)-based vaccines are being developed for treatment of patients with cancer, in part because DC are potent inducers of CD8+ CTL. DC MHC class I:antigenic peptide complexes that are required for CTL elicitation are most often generated by incubating DC with peptides or by transfecting (or transducing) DC with cDNAs (or viral vectors) that encode protein Ags. The former approach is feasible when MHC class I Ags and relevant peptides are known. The latter approach may be hampered by inefficient DC transfection (transduction) and/or difficulties associated with preparation and use of viral vectors. Herein we demonstrate that a bacterial recombinant model tumor-associated Ag (OVA) that contains the HIV TAT protein transduction domain (PTD) was readily engineered and purified, efficiently transduced murine lymphocytes and DC, and was processed by proteasomes for MHC class I-restricted presentation to CTL. In addition, PTD-containing rOVA was processed and presented by DC to CD4 T cells as efficiently as native OVA or rOVA lacking the PTD. PTD-OVA-transduced DC induced CTL in vivo in a Th cell-independent fashion and vaccinated against OVA-expressing tumors. In contrast, rOVA lacking the PTD did not enter the DC MHC class I presentation pathway and DC treated with this protein did not prime OVA-specific CTL in vivo. Treatment of mice harboring clinically apparent OVA-expressing tumors with PTD-OVA-transduced DC resulted in tumor regression in some animals. This straightforward vaccination strategy may translate into DC-based treatments for patients with cancer and other serious diseases.
DOI：
10.1073/pnas.95.16.9482
发表时间：
1998-08-04
影响因子：
11.1
作者：
Fields, RC;Shimizu, K;Mulé, JJ
通讯作者：
Mulé, JJ