T-Cell Costimulation in the Design of Cancer Vaccines

癌症疫苗设计中的 T 细胞共刺激

• 批准号: 6559279
• 负责人: JEFFREY SCHLOM
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6559279
• 关键词: Poxviridae; T lymphocyte; antigen presenting cell; biological signal transduction; biotechnology; cytotoxic T lymphocyte; dendritic cells; drug design /synthesis /production; gene expression; laboratory mouse; leukocyte activation /transformation; neoplasm /cancer vaccine; neoplastic cell; transfection /expression vector; vaccine development; vaccinia virus; vector vaccine

The activation of T cells has been shown to require at least two signals via molecules present on professional antigen-presenting cells: signal 1 via a peptide/MHC complex, and signal 2 via a costimulatory molecule. Studies are being conducted on the impact of hyperexpression of multiple costimulatory molecules in the activation of T cells. Pox virus vectors (vaccinia and avipox) are being used because of their ability to efficiently express multiple transgenes. Murine tumor cells provided with signal 1 and infected with either recombinant vaccinia or avipox vectors containing a TRIad of COstimulatory Molecules (B7-1/ICAM-1/LFA-3, designated TRICOM) induce the activation of T cells to a far greater extent than cells infected with any one or two costimulatory molecules. Despite this T-cell "hyperstimulation" using TRICOM vectors, no evidence of apoptosis above that seen using the B7-1 vector was observed. Experiments using a four-gene construct have shown that TRICOM recombinants can enhance antigen-specific T-cell responses in vivo. Studies are also ongoing to determine if dendritic cells infected with these TRICOM vectors are rendered more efficient in enhancing T-cell responses. Peptide-pulsed dendritic cells infected with rF-TRICOM or rV-TRICOM induced cytotoxic T-lymphocyte activity in vitro and in vivo to a markedly greater extent than peptide-pulsed dendritic cells. These studies thus demonstrate the ability of vectors to introduce three costimulatory molecules into cells, thereby activating T-cell populations to levels far greater than those achieved with the use of one or two costimulatory molecules. This new threshold of T-cell activation in vaccine design is currently being studied.

T细胞的激活已被证明需要至少两个信号通过专业抗原呈递细胞上存在的分子：通过肽/MHC复合物信号1，以及通过共刺激分子信号2。正在对多种共刺激分子在T细胞激活中的过度X肌的影响进行研究。由于它们有效表达多个转基因的能力，因此使用了痘病毒载体（Vaccinia和avipox）。带有信号1的鼠类肿瘤细胞并被重组离子植物或抗蛋白脂蛋白载体感染，其中含有三合一的结肠刺激分子（B7-1/ICAM-1/LFA-3，指定为triCom）诱导T细胞的激活程度远大于感染任何一种或两种或两种costimulatimulation Molecules的细胞。尽管使用Tricom载体进行了T细胞“过度刺激”，但在上面尚未观察到使用B7-1载体的凋亡证据。使用四基因构建体的实验表明，三环体重组者可以在体内增强抗原特异性T细胞反应。正在进行研究以确定感染这些三角体载体的树突状细胞在增强T细胞反应方面的效率更高。与肽脉冲的树突状细胞相比，用RF-TRICOM或RV-TICOM感染的肽脉冲的树突状细胞在体外和体内诱导的细胞毒性T-淋巴细胞活性明显更大。因此，这些研究表明向量将三个共刺激分子引入细胞的能力，从而将T细胞种群激活到远大于使用一个或两个共刺激分子所达到的水平。目前正在研究疫苗设计中T细胞激活的新阈值。