Ackerstein A, Kedar E, Slavin S
Department of Bone Marrow Transplantation Hadassah University Hospital, Jerusalem, Israel.
Blood. 1991 Sep 1;78(5):1212-5.
Unlike allogeneic bone marrow transplantation (BMT), autologous BMT is not accompanied by immune-mediated graft-versus-leukemia (GVL) effects; hence, the relapse rate observed after autologous BMT in malignant hematologic disorders is higher than that observed after allogeneic BMT. Autologous BMT represents a much safer medical procedure available for many patients in need in situations where allogeneic BMT is not feasible or risky. The present experiments were designed to investigate whether it might be possible to combine the therapeutic benefits of autologous BMT with additional immunotherapy after BMT. The tumor model used for investigating GVL effects was the murine B-cell leukemia (BCL1), a spontaneous, nonimmunogenic, highly lethal leukemia of BALB/c origin. BALB/c mice inoculated with 10(3) BCL1 leukemia cells were treated on day-1 with cyclophosphamide 100 mg/kg and transplanted with normal syngeneic BM cells on day 0. High-dose recombinant interleukin-2 (rIL-2) (100,000 Cetus units x 3/day intraperitoneally x 5 consecutive days) was initiated on day +1, +7, or +21 after BMT. Kinetics of lymphocyte reconstitution after syngeneic BMT indicated a steep increase in the absolute number of peripheral blood lymphocytes on days 17 through 24. All experimental groups were observed for relapse. Mice receiving no rIL-2 therapy relapsed and died within 50 days after BMT, whereas mice receiving rIL-2 showed long-term disease-free survival. Optimal time for administration of rIL-2 was noted at 3 weeks post-BMT, with 90% of the mice surviving with no evidence of disease for more than 1 year. Similarly, when 10(4) BCL1 cells were given 1 day after syngeneic BMT to simulate minimal residual disease after syngeneic BMT, rIL-2 therapy administered at 14 days post-BMT seemed effective in prolonging disease-free survival in contrast to the same regimen given at 1 day after BMT. Our data suggest that immunotherapy with rIL-2 should be further investigated as a new immunotherapeutic tool for decreasing the relapse rate after BMT for hematologic malignancies.
与异基因骨髓移植（BMT）不同，自体BMT不会伴随免疫介导的移植物抗白血病（GVL）效应；因此，在恶性血液系统疾病中，自体BMT后观察到的复发率高于异基因BMT后观察到的复发率。自体BMT对于许多有需求但异基因BMT不可行或有风险的患者来说是一种安全得多的医疗程序。本实验旨在研究是否有可能将自体BMT的治疗益处与BMT后的额外免疫疗法相结合。用于研究GVL效应的肿瘤模型是小鼠B细胞白血病（BCL1），这是一种起源于BALB/c的自发性、非免疫原性、高度致死性白血病。接种10³个BCL1白血病细胞的BALB/c小鼠在第 -1天接受100 mg/kg环磷酰胺治疗，并在第0天移植正常同基因骨髓细胞。在BMT后第 +1、+7或 +21天开始给予高剂量重组白细胞介素 -2（rIL-2）（100,000 赛特斯单位×3/天腹腔注射×连续5天）。同基因BMT后淋巴细胞重建动力学表明，外周血淋巴细胞绝对数量在第17天至24天急剧增加。观察所有实验组的复发情况。未接受rIL-2治疗的小鼠在BMT后50天内复发并死亡，而接受rIL-2治疗的小鼠显示出长期无病生存。rIL-2的最佳给药时间为BMT后3周，90%的小鼠存活且无疾病迹象超过1年。同样，当在同基因BMT后1天给予10⁴个BCL1细胞以模拟同基因BMT后的微小残留病时，与在BMT后1天给予相同方案相比，在BMT后14天给予rIL-2治疗似乎有效地延长了无病生存期。我们的数据表明，rIL-2免疫疗法作为一种降低血液系统恶性肿瘤BMT后复发率的新免疫治疗工具应进一步研究。
