Daniel P T, Kroidl A, Kopp J, Sturm I, Moldenhauer G, Dörken B, Pezzutto A
Max Delbrück Center for Molecular Medicine, Berlin-Buch, Germany.
Blood. 1998 Dec 15;92(12):4750-7.
Bispecific antibodies (CD3x19) against the CD3epsilon-chain of the T-cell-receptor/CD3 complex and the CD19 antigen on B cells can target polyclonal, nontumor-specific T cells to B lymphoma cells. This induces T-cell activation, and generation of cytotoxic T cells (CTLs). These polyclonal CTLs, targeted by the CD3x19 bispecific antibodies, can lyse CD19(+) B-lymphoma cells. In a xenotransplant model in severe combined immunodeficiency deficient (SCID) mice, we and others observed that CD28 triggering is required for efficient elimination of B-lymphoma cells and cure from the tumor in addition to CD3x19 administration. We also showed that the activation and targeting of CTLs to the target cell by signal one alone, ie, the CD3x19 mab, induces T-cell death by apoptosis. In blocking experiments we showed that this "veto" apoptosis is mediated by the CD95/Fas ligand. Addition of anti-CD28 (signal 2) renders the T cells resistant for veto apoptosis both in vitro and in vivo. We therefore conclude that the role of costimulation in immunotherapy with bispecific antibodies or other T-cell-based immune strategies is not only to facilitate T-cell activation but also to prevent T-cell deletion by apoptosis.
针对T细胞受体/CD3复合物的CD3ε链和B细胞上CD19抗原的双特异性抗体（CD3x19）可将多克隆、非肿瘤特异性T细胞靶向B淋巴瘤细胞。这会诱导T细胞活化，并产生细胞毒性T细胞（CTL）。这些由CD3x19双特异性抗体靶向的多克隆CTL可裂解CD19(+) B淋巴瘤细胞。在严重联合免疫缺陷（SCID）小鼠的异种移植模型中，我们和其他人观察到，除了给予CD3x19外，有效消除B淋巴瘤细胞和治愈肿瘤还需要CD28共刺激。我们还表明，仅通过信号一（即CD3x19单克隆抗体）将CTL激活并靶向靶细胞会诱导T细胞通过凋亡死亡。在阻断实验中我们表明，这种“否决”性凋亡是由CD95/Fas配体介导的。添加抗CD28（信号2）可使T细胞在体外和体内对否决性凋亡产生抗性。因此，我们得出结论，共刺激在双特异性抗体免疫治疗或其他基于T细胞的免疫策略中的作用不仅是促进T细胞活化，还在于防止T细胞因凋亡而缺失。
