Long G S, Hiserodt J C, Harnaha J B, Cramer D V
Department of Pathology, University of Pittsburgh School of Medicine, Pennsylvania 15261.
Transplantation. 1988 Sep;46(3):433-8. doi: 10.1097/00007890-198809000-00020.
We have studied the effect of using lymphokine-activated killer (LAK) cells as an in vitro means for eliminating leukemic cells from normal bone marrow prior to transplantation of experimental animals. Rat LAK cells exhibit broad cytolytic activity against a variety of hematopoietic neoplasms, but do not kill normal bone marrow cells or lectin-stimulated blasts. Bone marrow was harvested from normal Fischer 344 rats, combined with increasing numbers of CRNK-16 tumor cells, and then incubated with LAK cells. The BM/tumor/LAK mixture was then administered to untreated Fischer rats, and the ability of the LAK cells to purge the bone marrow of neoplastic cells and prevent the transmission of the leukemia to recipient animals monitored. Our results demonstrate that LAK cells are capable of efficiently purging the bone marrow of neoplastic cells. Treatment of the BM/tumor mixtures with LAK cells is associated with significant prolongation of survival in the higher tumor doses (10(5) tumor cells/recipient) and complete elimination of the tumor in a high percentage of recipients at lower tumor levels (10(3)-10(4) tumor cells/recipient). At levels of BM transfer comparable to that used in humans, there was no evidence of a failure of LAK-treated bone marrow to reconstitute lethally conditioned recipient animals. However, with lower numbers of BM cells, there was an increased mortality in animals receiving LAK-treated BM, suggesting a minimal inhibition of pluripotent hematopoietic stem cell function when suboptimal numbers of BM cells are used for reconstitution. These experiments demonstrate that LAk cells are capable of eliminating neoplastic cells in bone marrow without significant destruction of immature syngeneic stem cells. LAK cells display a broad range of cytolytic activity against hematopoietic and solid tissue tumors, and are therefore capable of eliminating small numbers of tumor cells from a wide variety of neoplastic diseases of the marrow. The ability to detect and eliminate malignant cells, without interfering with reconstitution with donor marrow, suggests that immune therapy with LAK cells can be a relatively simple and efficient method to purge bone marrow prior to autologous transplantation in patients following high-dose chemotherapy for neoplastic diseases.
我们研究了使用淋巴因子激活的杀伤细胞（LAK细胞）作为一种体外方法，在实验动物移植前从正常骨髓中清除白血病细胞的效果。大鼠LAK细胞对多种造血系统肿瘤表现出广泛的细胞溶解活性，但不杀伤正常骨髓细胞或凝集素刺激的母细胞。从正常的Fischer 344大鼠获取骨髓，与数量不断增加的CRNK - 16肿瘤细胞混合，然后与LAK细胞一起孵育。接着将骨髓/肿瘤/LAK混合物给予未经处理的Fischer大鼠，并监测LAK细胞清除骨髓中肿瘤细胞以及防止白血病传播给受体动物的能力。我们的结果表明，LAK细胞能够有效地清除骨髓中的肿瘤细胞。用LAK细胞处理骨髓/肿瘤混合物，在较高肿瘤剂量（10⁵个肿瘤细胞/受体）时可显著延长生存期，在较低肿瘤水平（10³ - 10⁴个肿瘤细胞/受体）时，高比例的受体动物肿瘤被完全清除。在与人类使用水平相当的骨髓移植量时，没有证据表明经LAK处理的骨髓不能重建造血功能严重受损的受体动物。然而，当骨髓细胞数量较少时，接受LAK处理骨髓的动物死亡率增加，这表明当用于重建的骨髓细胞数量未达最佳时，多能造血干细胞功能受到最小程度的抑制。这些实验表明，LAK细胞能够在不显著破坏同基因未成熟干细胞的情况下清除骨髓中的肿瘤细胞。LAK细胞对造血系统和实体组织肿瘤表现出广泛的细胞溶解活性，因此能够从多种骨髓肿瘤性疾病中清除少量肿瘤细胞。能够检测和清除恶性细胞，同时不干扰供体骨髓的重建，这表明用LAK细胞进行免疫治疗可能是一种相对简单有效的方法，用于在肿瘤性疾病患者接受大剂量化疗后进行自体移植前清除骨髓中的肿瘤细胞。
