Antisera induced by infusions of autologous Ad-CD154-leukemia B cells identify ROR1 as an oncofetal,antigen and receptor for Wnt5a
Antisera induced by infusions of autologous Ad-CD154-leukemia B cells identify ROR1 as an oncofetal,antigen and receptor for Wnt5a
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DOI：
10.1073/pnas.0712148105
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发表时间：
2008-02-26
影响因子：
11.1
通讯作者：
Kipps, Thomas J.
中科院分区：
文献类型：
--
作者：
Fukuda, Tetsuya;Chen, Liguang;Kipps, Thomas J.
我们检查了6例患者的血清之前和之后静脉输注自体慢性淋巴细胞白血病（CLL）细胞转导的腺病毒编码CD 154（Ad-CD 154）离体。五名患者产生了高滴度的腺病毒抗体，三名患者产生了与白血病相关表面抗原（我们将其鉴定为ROR 1）反应的IgG。在未治疗患者的血清中未检测到抗ROR 1抗体。我们制备了抗ROR 1单克隆抗体，发现它们与所有患者的CLL细胞特异性反应，但不与非白血病性白细胞、各种正常成人组织或血液单核细胞（包括健康成人的CD 5（+）B细胞）反应。ROR 1可以结合Wnt 5a，当在HEK 293细胞中与ROR 1共表达时，Wnt 5a诱导NF-κ B活化，并增强CLL细胞的体外存活，这种作用可以被治疗后抗ROR 1抗血清中和。我们的结论是，CLL患者可以打破免疫耐受ROR 1，这是一个癌胚表面抗原和生存信号受体在这种肿瘤性疾病。
We examined the sera of six patients before and after i.v. infusions of autologous chronic lymphocytic leukemia (CLL) cells transduced ex vivo with an adenovirus encoding CD154 (Ad-CD154). Five patients made high-titer antibodies against adenovirus and three made IgG reactive with a leukemia-associated surface antigen, which we identified as ROR1. Anti-ROR1 antibodies were not detected in the sera of untreated patients. We generated anti-ROR1 mAbs and found they reacted specifically with the CLL cells of all patients, but not with nonleukemic leukocytes, a wide variety of normal adult tissues, or blood mononuclear cells, including CD5(+) B cells of healthy adults. ROR1 could bind Wnt5a, which induced activation of NF-kappa B when coexpressed with ROR1 in HEK293 cells and enhanced the survival of CLL cells in vitro, an effect that could be neutralized by posttreatment anti-ROR1 antisera. We conclude that patients with CLL can break immune tolerance to ROR1, which is an oncofetal surface antigen and survival-signaling receptor in this neoplastic disease.