Institute of Immunology, Medical Faculty Carl Gustav Carus, Technical University Dresden, Fetscherstr. 74, 01307 Dresden, Germany.
J Autoimmun. 2013 May;42:105-16. doi: 10.1016/j.jaut.2013.01.002. Epub 2013 Jan 22.
The nuclear autoantigen La can be detected on the surface of dying cells. Here we present an assay which enables us to show that La protein is not limited to the surface of dying cells but will be released upon stress-induced cell death. As released La protein tightly binds to the surface of neighboring intact cells we asked the question whether or not La protein could serve as a stress-inducible target e.g. for redirecting of regulatory T cells (Tregs) into damaged tissues to downregulate an immune response. In order to provide first proof of concept we developed a novel fully humanized single-chain bispecific antibody (bsAb) which on the one hand is directed to the La antigen and on the other hand to the CD3 complex of T cells. A cross-linkage of Tregs with La-decorated target cells mediated by this bsAb resulted indeed in the activation of the Tregs in a target-dependent manner. Moreover, such bsAb activated Tregs displayed a potent suppressive capacity and negatively influenced proliferation, expansion and cytokine production of autologous CD4(+) and CD8(+) Teff cells.
核抗原 La 可以在濒死细胞的表面被检测到。在这里，我们提出了一种检测方法，使我们能够证明 La 蛋白不仅局限于濒死细胞的表面，而且在应激诱导的细胞死亡时会被释放。由于释放的 La 蛋白与邻近完整细胞的表面紧密结合，我们不禁要问，La 蛋白是否可以作为一种应激诱导的靶标，例如将调节性 T 细胞（Tregs）重新定向到受损组织中，以下调免疫反应。为了提供第一个概念验证，我们开发了一种新型的完全人源化单链双特异性抗体（bsAb），它一方面针对 La 抗原，另一方面针对 T 细胞的 CD3 复合物。通过这种 bsAb 将 Tregs 与带有 La 修饰的靶细胞交联，确实以靶细胞依赖的方式激活了 Tregs。此外，这种 bsAb 激活的 Tregs 表现出强大的抑制能力，并负调控自身 CD4(+)和 CD8(+)Teff 细胞的增殖、扩增和细胞因子产生。
