Generation of tumor-specific cytotoxic T lymphocyte and prolongation of the survival of tumor-bearing mice using interleukin-18-secreting fibroblasts loaded with an epitope peptide
Generation of tumor-specific cytotoxic T lymphocyte and prolongation of the survival of tumor-bearing mice using interleukin-18-secreting fibroblasts loaded with an epitope peptide
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DOI：
10.1016/j.vaccine.2003.12.015
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发表时间：
2004-06-30
期刊：
影响因子：
5.5
通讯作者：
Kim, TS
中科院分区：
文献类型：
--
作者：
Chung, SW;Cohen, EP;Kim, TS
目前对产生针对肿瘤抗原的细胞毒性T淋巴细胞（CTL）应答作为癌症的治疗有很大兴趣。在这项研究中，对小鼠成纤维细胞（H-2（B））进行遗传修饰以表达共刺激B7.1和成熟白细胞介素（IL）-18，然后加载卵清蛋白（OVA）表位（SIINFEKL，H-2K（B）限制性）作为模型抗原，并测试在C57 BL/6小鼠（H-2 B）中对OVA特异性CTL的诱导。还构建了缺乏IL-18或B7.1的遗传修饰的成纤维细胞。用IL-18/B7.1转染的成纤维细胞免疫诱导了针对表达OVA的EL 4（EG 7）肿瘤细胞的强细胞毒活性，但不针对其它H-2b肿瘤细胞如EL 4、C1498和B16 F1细胞。用IL-18/137.1转染的成纤维细胞的小鼠中的细胞毒性应答的幅度显著高于用任何其它细胞构建体免疫的小鼠中的应答。在用IL-18/B7.1转染的成纤维细胞免疫的小鼠中，具有OVA特异性细胞毒活性的CD 8（+）T细胞占优势。此外，用IL-18/B7.1转染的成纤维细胞治疗显著延长了携带EG 7肿瘤的小鼠的存活期。IL-18/137.1转染的成纤维细胞在不需要宿主抗原提呈细胞（APC）和NK 1.1（+）细胞的情况下也能诱导抗肿瘤CTL免疫，但在诱导阶段去除CD 4（+）T细胞会部分降低CTL免疫。这些结果支持IL-18/137.1基因转移增强成纤维细胞诱导抗原特异性CTL应答的抗原呈递能力的能力。(C)2004 Elsevier Ltd.保留所有权利。
There is currently much interest in generating cytotoxic T lymphocyte (CTL) responses against tumor antigens as a therapy for cancer. In this study mouse fibroblasts (H-2(b)) were genetically modified to express a costimulatory B7.1 and a mature interleukin (IL)-18, and then loaded with an ovalbumin (OVA) epitope (SIINFEKL, H-2K(b) restricted) as a model antigen, and tested for the induction of OVA-specific CTLs in C57BL/6 mice (H-2b). The genetically modified fibroblasts lacking either IL-18 or B7.1 were also constructed. Immunization with the IL-18/B7.1-transfected fibroblasts induced strong cytotoxic activities against OVA-expressing EL4 (EG7) tumor cells, but not against other H-2b tumor cells such as EL4, C1498, and B16F1 cells. The magnitude of the cytotoxic response in mice with the IL-18/137.1-transfected fibroblasts was significantly higher than the response in mice immunized with any other cell constructs. CD8(+) T cells with OVA-specific cytotoxic activities were predominant in mice immunized with the IL-18/B7.1-transfected fibroblasts. Furthermore, treatment with the IL-18/B7.1-transfected fibroblasts significantly prolonged the survival period of EG7 tumor-bearing mice. Anti-tumor CTL immunity by the IL-18/137.1-transfected fibroblasts could be induced without the help of host antigen-presenting cells (APCs) and NK1.1(+) cells, whereas partially decreased by the depletion of CD4(+) T cells at the inductive stage. These results support the ability of IL-18/137.1 gene transfer to enhance the antigen-presenting capacity of fibroblasts for inducing antigen-specific CTL response. (C) 2004 Elsevier Ltd. All rights reserved.