Maeda Akiko, Maeda Tadao, Ohguro Hiroshi, Palczewski Krzysztof, Sato Noriyuki
Department of Ophthalmology, University of Washington, Seattle, WA 98195-6485, USA.
Eur J Immunol. 2002 Aug;32(8):2300-7. doi: 10.1002/1521-4141(200208)32:8<2300::AID-IMMU2300>3.0.CO;2-7.
Recoverin (Rec)-specific CTL present in peripheral blood recognize Rec-expressing tumor cells of patients with cancer-associated retinopathy (CAR), a paraneoplastic retinopathy syndrome. To evaluate the effects of Rec on retina and cancer cells, we generated an experimental mouse model, tested the induction of Rec-specific anti-tumor CTL, and analyzed retinal function using electroretinogram (ERG) in these animals. We observed a Rec-specific CTL response in BALB/c mice and significant growth inhibition of Rec-expressing syngeneic MethA fibrosarcoma cells in vivo. R64 (AYAQHVFRSF) peptide, derived from Rec that induces anti-tumor CTL in humans, produced anti-tumor effects in BALB/c mice. Furthermore, elevated anti-Rec antibodies correlated with decreased ERG amplitudes in Rec, Rec-expressing tumor and R64-treated mice. These data suggest that Rec contains amino acid sequences which cause retinal dysfunction, but they also induce anti-tumor CTL and tumor regression. These observations describe initial characterization of the CAR mouse model, a necessary step in developing new insight into immunological mechanisms of paraneoplastic syndromes and tumor immunity for potential immunotherapeutic approaches to cancer.
存在于外周血中的恢复蛋白（Rec）特异性细胞毒性T淋巴细胞（CTL）可识别患有癌症相关性视网膜病变（CAR，一种副肿瘤性视网膜病变综合征）患者的表达Rec的肿瘤细胞。为了评估Rec对视网膜和癌细胞的影响，我们建立了一个实验性小鼠模型，检测Rec特异性抗肿瘤CTL的诱导情况，并在这些动物中使用视网膜电图（ERG）分析视网膜功能。我们在BALB/c小鼠中观察到了Rec特异性CTL反应，并且在体内观察到表达Rec的同基因MethA纤维肉瘤细胞的显著生长抑制。源自Rec的R64（AYAQHVFRSF）肽在人类中可诱导抗肿瘤CTL，在BALB/c小鼠中也产生了抗肿瘤作用。此外，在Rec、表达Rec的肿瘤和R64处理的小鼠中，抗Rec抗体水平升高与ERG振幅降低相关。这些数据表明，Rec含有导致视网膜功能障碍的氨基酸序列，但它们也能诱导抗肿瘤CTL和肿瘤消退。这些观察结果描述了CAR小鼠模型的初步特征，这是深入了解副肿瘤综合征的免疫机制和肿瘤免疫以开发潜在癌症免疫治疗方法的必要步骤。
