Thirdborough Stephen M, Radcliffe Joanna N, Friedmann Peter S, Stevenson Freda K
Molecular Immunology Group, Tenovus Laboratory, Southampton University Hospitals Trust, Southampton SO16 6YD, United Kingdom.
Cancer Res. 2002 Mar 15;62(6):1757-60.
The clonotypic T-cell antigen receptor (TCR) provides unique Valpha and Vbeta sequences with potential as idiotypic targets for immunoregulation. For T-cell malignancies, vaccination with the TCR could induce therapeutic anti-idiotypic responses. To facilitate this approach, we have developed DNA vaccines that include the genes encoding TCR sequences from a T-cell lymphoma (TCL). To combine requirements for stable folding with a simple minimized single-chain construction, we used a three-domain ValphaVbetaCbeta sequence. To promote anti-TCR immunity, we fused a pathogen-derived sequence from tetanus toxin to the 3'-end of the single-chain TCR. The fusion gene vaccine induced anti-idiotypic antibodies and generated protection against the TCL. The critical requirement for the conformational integrity of the delivered TCR antigen was highlighted by the observation that DNA fusion vaccines containing either ValphaVbeta or VbetaCbeta sequences failed to generate antibodies reactive with the native TCR or provide protection. This is the first report of a DNA vaccine able to induce anti-idiotypic immunity against TCL, and it presents a simple strategy for selectively eliminating T-cell clones in vivo.
克隆型T细胞抗原受体（TCR）提供了独特的Vα和Vβ序列，具有作为免疫调节独特型靶点的潜力。对于T细胞恶性肿瘤，用TCR进行疫苗接种可诱导治疗性抗独特型反应。为了促进这种方法，我们开发了DNA疫苗，其中包含编码来自T细胞淋巴瘤（TCL）的TCR序列的基因。为了将稳定折叠的要求与简单的最小化单链结构相结合，我们使用了三结构域VαVβCβ序列。为了促进抗TCR免疫，我们将破伤风毒素的病原体衍生序列融合到单链TCR的3'末端。融合基因疫苗诱导了抗独特型抗体，并产生了针对TCL的保护作用。含有VαVβ或VβCβ序列的DNA融合疫苗未能产生与天然TCR反应的抗体或提供保护，这一观察结果突出了所递送的TCR抗原构象完整性的关键要求。这是关于能够诱导针对TCL的抗独特型免疫的DNA疫苗的首次报道，并且它提出了一种在体内选择性消除T细胞克隆的简单策略。
