HLA-A*0201-restricted CTL epitope of a novel osteosarcoma antigen, papillomavirus binding factor.
HLA-A*0201-restricted CTL epitope of a novel osteosarcoma antigen, papillomavirus binding factor.
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DOI：
10.1186/1479-5876-7-44
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发表时间：
2009-06-12
影响因子：
7.4
通讯作者：
Sato N
中科院分区：
文献类型：
--
作者：
Tsukahara T;Kawaguchi S;Torigoe T;Takahashi A;Murase M;Kano M;Wada T;Kaya M;Nagoya S;Yamashita T;Sato N
为了开发基于多肽的骨肉瘤免疫疗法，我们先前在人类白细胞抗原B55的背景下确定了乳头瘤病毒结合因子(PBF)是一种CTL定义的骨肉瘤抗原。然而，基于PBF的免疫治疗的临床应用需要在更常见的HLA分子如HLA-A2的背景下鉴定骨肉瘤细胞中自然呈现的CTL表位。根据BIMAS评分，从PBF的氨基酸序列中合成了10个具有HLA-A*0201结合基序的多肽，并用人类白细胞抗原I类稳定实验进行了筛选。采用极限稀释法(LD)/混合淋巴细胞肽培养法(MLPC)和四聚体频率分析法检测了5例HLAA0201+骨肉瘤患者外周血中识别所选PBF衍生肽的CTL频率。通过有限稀释和单细胞分选相结合的方法，试图从四聚体阳性CTL池中建立PBF特异性CTL克隆。用~(51)Cr释放法检测CTL的细胞毒作用。多肽PBF A2.2与人类白细胞抗原A*0201的亲和力最高。5例患者中有3例检测到CD8+T细胞与PBF A2.2多肽反应，频率为2×10-7~5×10-6。一种四聚体阳性的PBF A2.2特异性CTL株5A9特异性地裂解了既表达PBF又表达HLA-A*0201或HLA-A*0206的同种异体骨肉瘤细胞系、自体肿瘤细胞以及经PBF A2.2冲击的T2细胞。在12个四聚体阳性的CTL克隆中，有5个克隆还裂解了同时表达PBF和HLA-A*0201或HLA-A*0206的同种异体骨肉瘤细胞株，并用PBF A2.2冲击T2。这些发现表明，PBF A2.2在人类白细胞抗原-A*0201和潜在的人类白细胞抗原-A*0206的背景下，作为骨肉瘤细胞的CTL表位。这扩大了PBF衍生的治疗性多肽疫苗对骨肉瘤患者的可获得性。
To develop peptide-based immunotherapy for osteosarcoma, we previously identified papillomavirus binding factor (PBF) as a CTL-defined osteosarcoma antigen in the context of HLA-B55. However, clinical application of PBF-based immunotherapy requires identification of naturally presented CTL epitopes in osteosarcoma cells in the context of more common HLA molecules such as HLA-A2. Ten peptides with the HLA-A*0201 binding motif were synthesized from the amino acid sequence of PBF according to the BIMAS score and screened with an HLA class I stabilization assay. The frequency of CTLs recognizing the selected PBF-derived peptide was determined in peripheral blood of five HLA-A*0201+ patients with osteosarcoma using limiting dilution (LD)/mixed lymphocyte peptide culture (MLPC) followed by tetramer-based frequency analysis. Attempts were made to establish PBF-specific CTL clones from the tetramer-positive CTL pool by a combination of limiting dilution and single-cell sorting. The cytotoxicity of CTLs was assessed by 51Cr release assay. Peptide PBF A2.2 showed the highest affinity to HLA-A*0201. CD8+ T cells reacting with the PBF A2.2 peptide were detected in three of five patients at frequencies from 2 × 10-7 to 5 × 10-6. A tetramer-positive PBF A2.2-specific CTL line, 5A9, specifically lysed allogeneic osteosarcoma cell lines that expressed both PBF and either HLA-A*0201 or HLA-A*0206, autologous tumor cells, and T2 pulsed with PBF A2.2. Five of 12 tetramer-positive CTL clones also lysed allogeneic osteosarcoma cell lines expressing both PBF and either HLA-A*0201 or HLA-A*0206 and T2 pulsed with PBF A2.2. These findings indicate that PBF A2.2 serves as a CTL epitope on osteosarcoma cells in the context of HLA-A*0201, and potentially, HLA-A*0206. This extends the availability of PBF-derived therapeutic peptide vaccines for patients with osteosarcoma.
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影响因子：
6.4
作者：
Imai, N;Harashima, N;Itoh, K
通讯作者：
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