Glass B, Uharek L, Zeis M, Loeffler H, Mueller-Ruchholtz W, Gassmann W
Department of Internal Medicine II, University of Kiel, Germany.
Br J Haematol. 1996 May;93(2):412-20. doi: 10.1046/j.1365-2141.1996.4941035.x.
We have investigated graft-versus-leukaemia (GVL) effects after allogeneic bone marrow transplantation (BMT), using three murine leukaemia models, A20 (B lymphocytic), WEHI-3 (myelomonocytic) and PU5-1R (myeloid). Injection of leukaemia cells in a high number (10(6) cells) into syngeneic Balb/c mice (H-2d) invariably led to death with a median survival time of 22 d (A20), 18 d (WEHI-3) and 45 d (PU5-1R). A lower tumour load of A20 (5 x 10(5) cells) was used in some experiments resulting in a leukaemic death rate of 94%. Lethal total-body irradiation followed by syngeneic BMT prolonged survival (P<0.05) for animals bearing the leukaemia A20 and WEHI-3 but was unsuccessful for animals injected with cells from the monocytic leukaemia PU5-1R. Graft-versus-host (GVH)-nonreactive marrow of (C57 x Balb/c)F1 mice (H2bxd) exerted a significant GVL-effect with reduced relapse rate and improved survival in mice receiving the leukaemia cell line A20. In animals with low tumour load a significant reduction of the relapse rate from 82% following syngeneic BMT to 47% following allogeneic, GVH-nonreactive BMT could be achieved. Depletion of natural killer (NK) cells from the GVL-reactive semi-allogenic bone marrow graft enhances the relapse rate of the leukaemia A20 to 65%. In mice bearing the leukaemias WEHI-3 or PU5-1R allogeneic GVH-nonreactive BMT did not improve survival compared to syngeneic BMT. Transplantation of GVH-reactive bone marrow from DBA mice (MHC identical to Balb/c, minor difference) caused only a limited and insignificant reduction of relapse rate for animals with the leukaemia A20. These in vivo data are in close correlation with in vitro natural killer cell (NK) activity of the donor strains against the respective leukaemia targets. Depletion of NK cells from the GVL-reactive (C57 x Balb/c)F1 bone marrow resulted in a significant loss of GVL activity. We conclude that NK cells are involved in graft-versus-leukaemia effects independent of graft-versus-host disease (GVHD).
我们使用三种小鼠白血病模型（A20，B淋巴细胞性；WEHI-3，髓单核细胞性；PU5-1R，髓性）研究了异基因骨髓移植（BMT）后的移植物抗白血病（GVL）效应。向同基因Balb/c小鼠（H-2d）大量注射白血病细胞（10⁶个细胞）总会导致死亡，A20模型的中位生存时间为22天，WEHI-3模型为18天，PU5-1R模型为45天。在一些实验中使用了较低肿瘤负荷的A20（5×10⁵个细胞），白血病死亡率为94%。致死性全身照射后进行同基因BMT可延长携带白血病A20和WEHI-3的动物的生存期（P<0.05），但对注射单核细胞白血病PU5-1R细胞的动物无效。（C57×Balb/c）F1小鼠（H2bxd）的移植物抗宿主（GVH）无反应性骨髓对接受白血病细胞系A20的小鼠产生了显著的GVL效应，复发率降低，生存期延长。在肿瘤负荷低的动物中，可实现复发率从同基因BMT后的82%显著降低至异基因、GVH无反应性BMT后的47%。从具有GVL反应性的半同种异体骨髓移植物中去除自然杀伤（NK）细胞会使白血病A20的复发率提高到65%。在携带白血病WEHI-3或PU5-1R的小鼠中，与同基因BMT相比，异基因GVH无反应性BMT并未改善生存期。移植来自DBA小鼠（MHC与Balb/c相同，有微小差异）的GVH反应性骨髓仅使患有白血病A20的动物的复发率有有限且不显著的降低。这些体内数据与供体菌株针对各自白血病靶标的体外自然杀伤细胞（NK）活性密切相关。从具有GVL反应性的（C57×Balb/c）F1骨髓中去除NK细胞会导致GVL活性显著丧失。我们得出结论，NK细胞参与了独立于移植物抗宿主病（GVHD）的移植物抗白血病效应。
