Condiotti R, Slavin S, Barak V, Nagler A
Department of Bone Marrow Transplantation, Hadassah University Hospital, Jerusalem, Israel.
Leuk Res. 1996 Jan;20(1):57-63. doi: 10.1016/0145-2126(95)00110-7.
Donor-derived cell-mediated immunotherapy has been shown to be an effective tool for reinduction of remission in chronic myeloid leukaemia (CML) patients who have relapsed post-bone marrow transplantation (BMT). Linomide, quinoline-3-carboxamine (LS 2616), is a new immunomodulator shown to increase the number of NK precursors in mice in addition to upregulating the quantity of CD56(+), CD3(-) and CD16(+) NK cells in the peripheral blood of patients following autologous BMT (ABMT). We investigated the in vitro effects of Linomide on NK activity of normal human donors. Large granular lymphocytes (LGLs) and NK cells were incubated overnight with Linomide (0.02-4.8 mg/ml), recombinant human interleukin-2 (IL-2, 75 IU/ml), or a combination of both. Linomide, at 0.02-0.3 mg/ml, augmented IL-2-induced proliferation of LGLs and NK cells in an inversely proportional manner. In contrast, Linomide at 0.6-4.8 mg/ml inhibited IL-2-induced proliferation of LGLs and NK cells in a dose-dependent manner. Linomide was able to potentiate phytohemaglutinin-induced CD3(+) cell proliferation. In addition, supernatants derived from Linomide treated CD3(+) T cells were able to mimic the direct stimulatory effect of Linomide on activated NK cell proliferation. These supernatants were found to have low levels of tissue necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL-1) and therefore Linomide stimulation of NK and T cell proliferation may be due to its inhibitory effect on the secretion of these cytokines by activated CD3(+) T cells. Linomide had no effect on cytotoxicity nor on the phenotypic expression of resting and IL-2-activated LGLs or NK cells. In view of our results, Linomide could possibly play a potential role in adoptive cell-mediated immunotherapy post-BMT.
供体来源的细胞介导免疫疗法已被证明是一种有效的工具，可用于诱导慢性髓性白血病（CML）患者在骨髓移植（BMT）后复发时再次缓解。利诺米德，喹啉 - 3 - 甲酰胺（LS 2616），是一种新型免疫调节剂，除了能上调自体骨髓移植（ABMT）患者外周血中CD56(+)、CD3(-)和CD16(+) NK细胞的数量外，还能增加小鼠体内NK前体细胞的数量。我们研究了利诺米德对正常人供体NK活性的体外影响。将大颗粒淋巴细胞（LGLs）和NK细胞与利诺米德（0.02 - 4.8 mg/ml）、重组人白细胞介素 - 2（IL - 2，75 IU/ml）或两者组合孵育过夜。0.02 - 0.3 mg/ml的利诺米德以反比方式增强IL - 2诱导的LGLs和NK细胞增殖。相比之下，0.6 - 4.8 mg/ml的利诺米德以剂量依赖方式抑制IL - 2诱导的LGLs和NK细胞增殖。利诺米德能够增强植物血凝素诱导的CD3(+)细胞增殖。此外，经利诺米德处理的CD3(+) T细胞的上清液能够模拟利诺米德对活化NK细胞增殖的直接刺激作用。发现这些上清液中组织坏死因子 - α（TNF - α）和白细胞介素 - 1（IL - 1）水平较低，因此利诺米德对NK和T细胞增殖的刺激可能是由于其对活化的CD3(+) T细胞分泌这些细胞因子的抑制作用。利诺米德对细胞毒性以及静息和IL - 2活化的LGLs或NK细胞的表型表达均无影响。鉴于我们的结果，利诺米德可能在BMT后的过继性细胞介导免疫疗法中发挥潜在作用。
