Leshem B, Vourka-Karussis U, Slavin S
Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Cytokines Cell Mol Ther. 2000 Sep;6(3):141-7. doi: 10.1080/mccm.6.3.141.147.
A model of mouse acute myeloid leukemia (mAML) was used to study the effector mechanism mediating the graft-versus-leukemia (GVL) effects in recipients of allogeneic bone marrow cells (BMC). mAML-bearing SJL/J (H-2s) mice were lethally irradiated and then transplanted with a mixture of BMC and spleen cells (SC) derived from normal syngeneic or allogeneic mice. To augment the GVL effect, recipients were injected intraperitoneally with recombinant human interleukin-2 (rIL-2) (1.2 x 10(5) IU) for 3 consecutive days, starting one day post BMC + SC transplantation. Spleen cells from treated recipients were adoptively transferred to untreated secondary SJL/J mice to test for the existence of residual tumor cells. All the secondary recipients of SC from mAML-bearing SJL/J mice rescued with syngeneic (SJL/J) or allogeneic (B10.S) BMC+SC (H-2s) differing at minor antigens of the histocompatibility complex (MiHC) developed leukemia and died. In sharp contrast, none of the secondary recipients of SC obtained from identical mAML-bearing mice rescued with B10.S BMC + SC but activated in vivo with IL-2 developed leukemia. Adoptive recipients of SC obtained from mAML-bearing recipients of major histocompatibility complex (MHC)-disparate (C57BL/6, H-2b) cells remained free of leukemia regardless of the use of rIL-2. In parallel with the in vivo findings, a 4-day in vitro exposure of splenocytes to 6 x 10(3) IU/ml rIL-2 resulted in a 5- to 20-fold increase in the frequency of alloreactive cytotoxic T-lymphocyte (CTL) precursors (CTLp) across MiHC and MHC barriers and a 2- to 6-fold increase in their cytotoxic activity. Our data suggest that augmentation of GVL effects by rIL-2 may be due to CTL activation by rIL-2, not excluding the potential beneficial role of rIL-2-activated allogeneic natural killer cells and MHC non-restricted killer cells. Cumulatively, our results suggest potentially beneficial effects of rIL-2, when used jointly with bone marrow transplantation or allogeneic cell therapy, on eradication of leukemia.
利用小鼠急性髓系白血病（mAML）模型研究介导异基因骨髓细胞（BMC）受体移植物抗白血病（GVL）效应的效应机制。将携带mAML的SJL/J（H-2s）小鼠进行致死性照射，然后移植来自正常同基因或异基因小鼠的BMC和脾细胞（SC）混合物。为增强GVL效应，从BMC + SC移植后一天开始，连续3天给受体腹腔注射重组人白细胞介素-2（rIL-2）（1.2×10⁵ IU）。将经处理受体的脾细胞过继转移至未经处理的二级SJL/J小鼠，以检测残留肿瘤细胞的存在。所有接受来自携带mAML的SJL/J小鼠的SC的二级受体，用在组织相容性复合体（MiHC）次要抗原上不同的同基因（SJL/J）或异基因（B10.S）BMC+SC（H-2s）进行挽救，均发生白血病并死亡。形成鲜明对比的是，从用B10.S BMC + SC挽救但在体内用IL-2激活的相同携带mAML的小鼠获得的SC的二级受体中，没有一只发生白血病。无论是否使用rIL-2，接受来自主要组织相容性复合体（MHC）不相合（C57BL/6，H-2b）细胞的携带mAML的受体的SC的过继受体均未患白血病。与体内研究结果一致，脾细胞在体外4天暴露于6×10³ IU/ml rIL-2导致跨MiHC和MHC屏障的同种异体反应性细胞毒性T淋巴细胞（CTL）前体（CTLp）频率增加5至20倍，其细胞毒性活性增加2至6倍。我们的数据表明，rIL-2增强GVL效应可能是由于rIL-2激活CTL，不排除rIL-2激活的异基因自然杀伤细胞和MHC非限制性杀伤细胞的潜在有益作用。总体而言，我们的结果表明，rIL-2与骨髓移植或异基因细胞治疗联合使用时，对根除白血病可能具有有益作用。
