Stohl W, Tovar Z, Talal N
Department of Medicine, University of Southern California, Los Angeles, 90033.
J Immunol. 1990 May 15;144(10):3718-25.
We have generated potent Ag-nonspecific cytolytic activity in PBMC cultures without exogenous IL-2 by stimulating the cells with anti-CD3 mAb. Three anti-CD3 mAb (147, 446, 454) each induced cytolytic activity against both K562 and Daudi targets, albeit to different degrees. The differences among the anti-CD3 mAb could not be explained by differences in their isotypes or avidity constants, by the number of anti-CD3 mAb molecules initially bound per cell, or by preferential or differential binding to TCR alpha/beta+ vs TCR gamma/delta+ cells. Each anti-CD3 mAb appeared to induce cytolytic activity via, in part, an IL-2-independent component, as evidenced by: 1) the generation of potent cytolytic activity in mAb 446-stimulated cultures despite undetectable IL-2 levels; 2) the frequent inability of exogenous IL-2 (10 U/ml) to generate as much cytolytic activity as that induced by mAb 147 or 454, despite the low levels of IL-2 (less than U/ml) in the latter cultures; and 3) the different kinetics in generation of cytolytic activity between IL-2 and anti-CD3 mAb. Moreover, exogenous IL-2 enhanced anti-CD3-induced cytolytic activity for each anti-CD3 mAb. However, IL-2-dependent processes also contributed to the generation of cytolytic activity, because anti-p55 IL-2R mAb in combination with anti-p75 IL-2R mAb partially inhibited generation of anti-CD3-induced cytolytic activity, albeit to a lesser degree than the inhibition by these anti-IL-2R mAb of generation of IL-2-induced cytolytic activity. By demonstrating the generation of potent cytolytic activity in the absence of exogenous IL-2, these studies may assist in the development of more effective and less toxic clinical adoptive immunotherapy protocols.
通过用抗CD3单克隆抗体刺激细胞，我们在没有外源性白细胞介素-2（IL-2）的外周血单核细胞（PBMC）培养物中产生了强大的抗原非特异性细胞溶解活性。三种抗CD3单克隆抗体（147、446、454）均诱导了针对K562和Daudi靶标的细胞溶解活性，尽管程度不同。抗CD3单克隆抗体之间的差异无法通过其同种型或亲和力常数的差异、每个细胞最初结合的抗CD3单克隆抗体分子数量，或与TCRα/β+与TCRγ/δ+细胞的优先或差异结合来解释。每种抗CD3单克隆抗体似乎部分通过不依赖IL-2的成分诱导细胞溶解活性，证据如下：1）尽管IL-2水平检测不到，但在单克隆抗体446刺激的培养物中仍产生了强大的细胞溶解活性；2）尽管后一种培养物中IL-2水平较低（低于U/ml），但外源性IL-2（10 U/ml）常常无法产生与单克隆抗体147或454诱导的细胞溶解活性一样多的活性；3）IL-2和抗CD3单克隆抗体在细胞溶解活性产生方面的动力学不同。此外，外源性IL-2增强了每种抗CD3单克隆抗体诱导的细胞溶解活性。然而，依赖IL-2的过程也有助于细胞溶解活性的产生，因为抗p55 IL-2R单克隆抗体与抗p75 IL-2R单克隆抗体联合部分抑制了抗CD3诱导的细胞溶解活性的产生，尽管程度低于这些抗IL-2R单克隆抗体对IL-2诱导的细胞溶解活性产生的抑制程度。通过证明在没有外源性IL-2的情况下产生了强大的细胞溶解活性，这些研究可能有助于开发更有效且毒性更小的临床过继性免疫治疗方案。
