Molecular transfer of CD40 and OX40 ligands to leukemic human B cells induces expansion of autologous tumor-reactive cytotoxic T lymphocytes
Molecular transfer of CD40 and OX40 ligands to leukemic human B cells induces expansion of autologous tumor-reactive cytotoxic T lymphocytes
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DOI：
10.1182/blood-2004-07-2556
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发表时间：
2005-03-15
期刊：
影响因子：
20.3
通讯作者：
Brenner, M
中科院分区：
文献类型：
--
作者：
Biagi, E;Dotti, G;Brenner, M
B 慢性淋巴细胞白血病 (B-CLL) 的单克隆抗体疗法的临床益处增加了开发针对该疾病的其他免疫疗法的兴趣。 CD40配体是T细胞激活的辅助信号，可以克服T细胞无反应性。 OX40-OX40配体途径参与记忆抗原特异性T细胞的后续扩增。我们利用过度表达这些配体的成纤维细胞的分子转移现象，在 B-CLL 细胞上表达 CD40L 和 OX40L。我们分析了修饰的 B-CLL 细胞对 7 名 B-CLL 患者自体 T 细胞的数量、表型和细胞毒功能的影响。在所有细胞中均观察到 CD40L 和 OX40L 的转移，随后 B7-1 和 B7-2 的上调。将表达 CD40L/OX40L 的 B-CLL 细胞与自体 T 细胞一起培养，产生 CD4(+)/CD8(+) 细胞毒性 T 细胞系，该细胞系响应自体 B-CLL 细胞或自体 T 细胞母细胞，分泌干扰素-γ (IFN-gamma) 和颗粒酶-B/穿孔素，但不响应同种异体 B-CLL 细胞或自体 T 细胞母细胞。单独使用 CD40L 或 OX40L 不足以扩增肿瘤反应性 T 细胞。 B-CLL 细胞上的 CD40L 和 OX40L 组合可能会产生针对 B-CLL 的治疗性免疫应答，无论是通过使用修饰的肿瘤细胞进行主动免疫，还是通过使用肿瘤反应性自体 T 细胞进行过继免疫治疗。 (c) 2005 年，美国血液学会。
Clinical benefits from monoclonal antibody therapy for B-chronic lymphocytic leukemia (B-CLL) have increased interest in developing additional immunotherapies for the disease. CD40 ligand is an accessory signal for T-cell activation and can overcome T-cell anergy. The OX40-OX40 ligand pathway is involved in the subsequent expansion of memory antigen-specific T cells. We expressed both CD40L and OX40L on B-CLL cells by exploiting the phenomenon of molecular transfer from fibroblasts overexpressing these ligands. We analyzed the effects of the modified B-CLL cells on the number, phenotype, and cytotoxic function of autologous T cells in 7 B-CLL patients. Transfer of CD40L and OX40L was observed in all and was followed by the up-regulation of B7-1 and B7-2. The culture of CD40L/OX40L-expressing B-CLL cells with autologous T cells generated CD4(+)/CD8(+) cytotoxic T-cell lines, which secreted interferon-gamma (IFN-gamma) and granzyme-B/perforin in response to autologous, but not to allogeneic, B-CLL cells or to autologous T-cell blasts. CD40L or OX40L alone was insufficient to expand tumor-reactive T cells. The combination of CD40L and OX40L on B-CLL cells may allow the generation of therapeutic immune responses to B-CLL, either by active immunization with modified tumor cells or by adoptive immunotherapy with tumor-reactive autologous T cells. (c) 2005 by The American Society of Hematology.