Cramer D V, Long G S
Department of Pathology, University of Pittsburgh School of Medicine, Pennsylvania 15261.
Prog Clin Biol Res. 1990;333:125-35; discussion 136-7.
The in vitro incubation of NK cells with the lymphokine IL-2 stimulates the development of a population of activated cytotoxic lymphocytes (LAK cells). These activated cells have the capacity to recognize and kill a wide range of neoplastic cells. The cytotoxic activity of LAK cells does not appear to be directed against normal, non-neoplastic cells and we have recently examined the potential for using LAK cells as a method of purging bone marrow for autologous transplantation in patients with widespread neoplastic diseases. We have utilized an experimental system consisting of the incubation of LAK cells from inbred F344 rats and normal bone marrow and demonstrated that this procedure does not interfere with the ability of the treated bone marrow to reconstitute lethally-conditioned recipients. The frequency and rate of reconstitution is the same in treatment and control groups, including incubation periods that extend up to 18 hours. When RNK-16 leukemia cell line (a spontaneous large granular lymphocyte leukemia that is syngeneic to the F344 strain) is added to the incubation mixture, the LAK cells have the ability in vitro to recognize the neoplastic cells and prevent the transmission of the leukemia to naive animals following bone marrow transplantation. As expected from the in vitro LAK cytotoxic activity, these activated cells are capable of recognizing and eliminating a variety of neoplasms. To date we have tested three different hematopoietic tumor lines derived from the F344 strain and one that was induced in an unrelated BN strain. In each case, the F344 LAK cells demonstrated an ability to prevent the transmission of a fatal leukemia and significantly prolong the survival of animals that had received larger numbers of neoplastic cells. The tumor lines examined included the RNK-16 line (NK cells), the Dunning leukemia (monocyte-lymphoblastic leukemia), a T-lymphocyte lymphoma and the acute myelogenous leukemia of BN rats (BN AML). Comparison of the results of these purging experiments to those seen when control animals are injected with graded doses of the individual tumors indicate that the LAK cells are eliminating approximately 2-3 logs of neoplastic cells. The ability of LAK cells to kill a wide range of tumors without damage to the ability of the recipient stem cells to reconstitute the bone marrow may allow for an important application for this type of purging technique in patients with neoplasms for which specific immunological or chemical therapies do not exist.
将自然杀伤细胞（NK细胞）与淋巴因子白细胞介素-2进行体外孵育，可刺激一群活化的细胞毒性淋巴细胞（淋巴因子激活的杀伤细胞，即LAK细胞）的发育。这些活化细胞有能力识别并杀死多种肿瘤细胞。LAK细胞的细胞毒性活性似乎并非针对正常的非肿瘤细胞，并且我们最近研究了将LAK细胞用作一种清除骨髓的方法的潜力，以便用于患有广泛性肿瘤疾病的患者进行自体移植。我们利用了一个实验系统，该系统包括将近交系F344大鼠的LAK细胞与正常骨髓进行孵育，并证明该程序不会干扰经处理的骨髓重建致死性预处理受体的能力。治疗组和对照组的重建频率和速率相同，包括长达18小时的孵育期。当将RNK - 16白血病细胞系（一种与F344品系同基因的自发性大颗粒淋巴细胞白血病）添加到孵育混合物中时，LAK细胞在体外有能力识别肿瘤细胞，并防止白血病在骨髓移植后传播给未接触过肿瘤的动物。正如从体外LAK细胞毒性活性所预期的那样，这些活化细胞能够识别并消除多种肿瘤。迄今为止，我们已经测试了三种源自F344品系的不同造血肿瘤细胞系以及一种在无关的BN品系中诱导产生的肿瘤细胞系。在每种情况下，F344 LAK细胞都表现出能够防止致命性白血病的传播，并显著延长接受大量肿瘤细胞的动物的存活时间。所检测的肿瘤细胞系包括RNK - 16细胞系（NK细胞）、邓宁白血病（单核细胞 - 淋巴细胞白血病）、一种T淋巴细胞淋巴瘤以及BN大鼠的急性髓性白血病（BN AML）。将这些清除实验的结果与给对照动物注射不同剂量的单个肿瘤时所观察到的结果进行比较表明，LAK细胞正在清除大约2 - 3个对数级的肿瘤细胞。LAK细胞能够杀死多种肿瘤而不损害受体干细胞重建骨髓的能力，这可能使这种清除技术在不存在特异性免疫或化学疗法的肿瘤患者中得到重要应用。
