端粒酶（hTERT 611 - 626）在B细胞慢性淋巴细胞白血病中作为肿瘤抗原，并自发产生抗白血病的细胞毒性T细胞。

Telomerase (hTERT 611-626) serves as a tumor antigen in B-cell chronic lymphocytic leukemia and generates spontaneously antileukemic, cytotoxic T cells.

作者信息

Kokhaei Parviz, Palma Marzia, Hansson Lotta, Osterborg Anders, Mellstedt Håkan, Choudhury Aniruddha

机构信息

Immune and Gene Therapy Lab, Cancer Centre Karolinska, Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden.

出版信息

Exp Hematol. 2007 Feb;35(2):297-304. doi: 10.1016/j.exphem.2006.10.006.

DOI:10.1016/j.exphem.2006.10.006

PMID:17258078

Abstract

OBJECTIVE

Human telomerase reverse transcriptase (hTERT) is the catalytic subunit of telomerase. In B-cell chronic lymphocytic leukemia (B-CLL), telomerase activity is increased in about 75% of patients. The aim of this study was to analyze whether B-CLL patients with telomerase-positive leukemic cells had naturally occurring, telomerase-specific T cells that might be utilized for immune-mediated lysis of autologous tumor cells.

METHODS

Spontaneous T-cell immunity and cytotoxicity against hTERT was explored in B-CLL. Nineteen of 25 B-CLL patients (76%) expressed hTERT (reverse transcriptase polymerase chain reaction) and 10 were selected for specific T-cell analysis against hTERT.

RESULTS

The stimulation index (SI) of T cells from seven telomerase-positive patients stimulated with a 16aa hTERT peptide (611-626) loaded onto dendritic cells (DC) was 33.9 +/- 15.4 (mean SI +/- standard error of mean) and 13.2 +/- 5.6 against a Ras control peptide (p = 0.05), whereas the corresponding SI values for three telomerase-negative patients were 5.3 +/- 5.3 against the hTERT 611-626 peptide and 10.3 +/- 6.5 against the Ras peptide, respectively; and for three healthy controls, 5.4 +/- 0.9 against the hTERT 611-626 peptide and 4.5 +/- 1.0 against the Ras peptide (both not significant). Blocking experiments revealed that the specific responses were major histocompatibility complex (MHC) class I and MHC class II restricted. DC pulsed with the hTERT-peptide generated MHC class I-restricted, hTERT-specific cytotoxic T lymphocytes in six of seven telomerase-positive patients; mean cytotoxicity of hTERT-stimulated T cells was 49.8% +/- 9.3% vs 13.1 +/- 2.9% for Ras-stimulated T cells (p < 0.05). In three of three telomerase-negative patients, no hTERT-specific cytotoxic T lymphocytes could be expanded.

CONCLUSION

Telomerase-positive B-CLL patients have spontaneously occurring cytotoxic hTERT-specific T cells. This antigen might be explored as a therapeutic vaccine in B-CLL.

摘要

目的

人端粒酶逆转录酶（hTERT）是端粒酶的催化亚基。在B细胞慢性淋巴细胞白血病（B-CLL）中，约75%的患者端粒酶活性升高。本研究的目的是分析端粒酶阳性白血病细胞的B-CLL患者是否具有天然存在的、端粒酶特异性T细胞，这些T细胞可能用于免疫介导的自体肿瘤细胞裂解。

方法

在B-CLL中探索针对hTERT的自发T细胞免疫和细胞毒性。25例B-CLL患者中有19例（76%）表达hTERT（逆转录酶聚合酶链反应），选择10例进行针对hTERT的特异性T细胞分析。

结果

用负载于树突状细胞（DC）上的16aa hTERT肽（611-626）刺激的7例端粒酶阳性患者的T细胞刺激指数（SI）为33.9±15.4（平均SI±平均标准误差），对Ras对照肽的刺激指数为13.2±5.6（p = 0.05），而3例端粒酶阴性患者对hTERT 611-626肽的相应SI值为5.3±5.3，对Ras肽的SI值为10.3±6.5；3例健康对照对hTERT 611-626肽的SI值为5.4±0.9，对Ras肽的SI值为4.5±1.0（均无统计学意义）。阻断实验表明，特异性反应受主要组织相容性复合体（MHC）I类和MHC II类限制。用hTERT肽脉冲的DC在7例端粒酶阳性患者中的6例中产生了MHC I类限制的、hTERT特异性细胞毒性T淋巴细胞；hTERT刺激的T细胞的平均细胞毒性为49.8%±9.3%，而Ras刺激的T细胞为13.1±2.9%（p < 0.05）。在3例端粒酶阴性患者中，未扩增出hTERT特异性细胞毒性T淋巴细胞。