Huang T H, Wu P Y, Lee C N, Huang H I, Hsieh S L, Kung J, Tao M H
Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
Blood. 2000 Dec 1;96(12):3663-70.
The idiotypic determinant (Id) of the immunoglobulin expressed by a B-cell malignancy can serve as an effective tumor-specific antigen but is only weakly immunogenic. This study demonstrates that the immunogenicity of the tumor Id protein can be dramatically increased by directing it to antigen-presenting cells (APCs). Cytotoxic T-lymphocyte antigen 4 (CTLA-4) present on activated T cells has a strong binding affinity to both B7-1 and B7-2 molecules, which are primarily expressed on APCs. After construction of a fusion protein consisting of Id and CTLA-4 (Id-CTLA4), mice immunized with the fusion protein induced high titers of Id-specific antibody and T-cell proliferative responses without adjuvants and were protected from lethal tumor challenge. The Id-CTLA4 fusion protein was so potent that even low doses (down to 0.1 microg) of the immunogen were able to elicit strong antibody responses. By using an Id-CTLA4 mutant protein, the ability to bind B7 molecules on APCs was shown to be required for the enhanced immunogenicity of Id-CTLA4. These findings demonstrate that fusing CTLA-4 to a potential tumor antigen represents an effective approach to prime antitumor immunities in vivo and may be applicable to the design of vaccines for a variety of other diseases. (Blood. 2000;96:3663-3670)
B细胞恶性肿瘤所表达免疫球蛋白的独特型决定簇（Id）可作为一种有效的肿瘤特异性抗原，但免疫原性较弱。本研究表明，将肿瘤Id蛋白导向抗原呈递细胞（APC）可显著增强其免疫原性。活化T细胞上的细胞毒性T淋巴细胞抗原4（CTLA-4）与主要在APC上表达的B7-1和B7-2分子具有很强的结合亲和力。构建由Id和CTLA-4组成的融合蛋白（Id-CTLA4）后，用该融合蛋白免疫的小鼠在无佐剂的情况下诱导出高滴度的Id特异性抗体和T细胞增殖反应，并受到保护免受致死性肿瘤攻击。Id-CTLA4融合蛋白效力很强，以至于即使低剂量（低至0.1微克）的免疫原也能引发强烈的抗体反应。通过使用Id-CTLA4突变蛋白，证明Id-CTLA4增强的免疫原性需要其与APC上B7分子的结合能力。这些发现表明，将CTLA-4与潜在肿瘤抗原融合是在体内引发抗肿瘤免疫的一种有效方法，可能适用于多种其他疾病疫苗的设计。（《血液》。2000年；96:3663 - 3670）
