Massaia M, Attisano C, Peola S, Montacchini L, Omedé P, Corradini P, Ferrero D, Boccadoro M, Bianchi A, Pileri A
Divisione Universitaria di Ematologia, Ospedale Maggiore S. Giovanni Battista, Università di Torino, Italy.
Blood. 1993 Sep 15;82(6):1787-97.
We have recently shown that peripheral blood T cells of multiple myeloma (MM) patients are very susceptible to stimulation of the T-cell receptor/CD3 complex with anti-CD3 monoclonal antibodies (MoAbs). CD3 stimulation is currently under clinical investigation as a nonspecific approach to boost antitumor effector mechanisms. The aim of this study was to determine whether the hyperreactivity of MM T cells to CD3 stimulation could be exploited to generate antitumor activity. Bone marrow mononuclear cells (BMMCs) from 65 MM patients were stimulated with the anti-CD3 MoAb OKT3 and the effect of this stimulation on autologous T cells and plasma cells was evaluated. The number of CD3+ CD25+ cells on day 6 was significantly higher in MM than the controls (30 normal individuals) (P = .001). Kinetic studies showed that 3H-thymidine incorporation peaked on day 3 and that the T-cell expansion peaked on days 5 and 6. In MM, T-cell activation markedly affected the survival of autologous plasma cells; their number in OKT3-treated cultures was significantly lower than in unstimulated cultures (P < .0001). T-cell activation and plasma cell decrease were not observed when T cells were removed from BMMC preparations. MM produced significantly higher levels of interferon-gamma (P = .005) and tumor necrosis factor-beta (P = .001), but lower levels of tumor necrosis factor-alpha (P < .001) than normal individuals. Interferon-gamma only was partially involved in CD3-induced plasma cell killing. Transwell cultures showed that the main mechanism by which CD3+ CD25+ cells affected plasma cells was direct cell-to-cell contact rather than cytokines. In conclusion, T cells in MM BMMCs possess distinct features in terms of susceptibility to CD3 stimulation and cytokine production compared with normal bone marrow T cells that can be exploited to generate antiplasma cell activity.
我们最近发现，多发性骨髓瘤（MM）患者的外周血T细胞极易受到抗CD3单克隆抗体（MoAb）对T细胞受体/CD3复合物的刺激。目前，CD3刺激作为一种增强抗肿瘤效应机制的非特异性方法正在进行临床研究。本研究的目的是确定是否可以利用MM T细胞对CD3刺激的高反应性来产生抗肿瘤活性。用抗CD3 MoAb OKT3刺激65例MM患者的骨髓单个核细胞（BMMC），并评估这种刺激对自体T细胞和浆细胞的影响。第6天时，MM患者CD3+CD25+细胞数量显著高于对照组（30名正常个体）（P = 0.001）。动力学研究表明，3H-胸腺嘧啶核苷掺入在第3天达到峰值，T细胞扩增在第5天和第6天达到峰值。在MM中，T细胞活化显著影响自体浆细胞的存活；OKT3处理的培养物中浆细胞数量显著低于未刺激的培养物（P < 0.0001）。当从BMMC制剂中去除T细胞时，未观察到T细胞活化和浆细胞减少。与正常个体相比，MM产生的干扰素-γ水平显著更高（P = 0.005），肿瘤坏死因子-β水平显著更高（P = 0.001），但肿瘤坏死因子-α水平更低（P < 0.001）。只有干扰素-γ部分参与CD3诱导的浆细胞杀伤。Transwell培养表明，CD3+CD25+细胞影响浆细胞的主要机制是直接的细胞间接触而非细胞因子。总之，与正常骨髓T细胞相比，MM BMMC中的T细胞在对CD3刺激的敏感性和细胞因子产生方面具有独特特征，可利用这些特征产生抗浆细胞活性。
