Gresser I, Greco G, Santini S M, Woodrow D, Mecchia M, Parlato S, Logozzi M, Venditti M, Maunoury M T, Belardelli F
Laboratory of Virology, Istituto Superiore di Sanità, Rome, Italy.
J Interferon Cytokine Res. 1998 Sep;18(9):667-79. doi: 10.1089/jir.1998.18.667.
ESb lymphoma cells injected i.v. into DBA/2 (H-2d) mice multiply rapidly in the liver and kill all mice in a few days. Adoptive transfer of allogeneic C57B1/6 (H-2b) tumor-immune or normal splenic lymphocytes to sublethally irradiated DBA/2 mice induced a marked antitumor state, graft-versus-leukemia (GVL), increasing the mean survival time 2-3-fold, but also induced an acute and lethal graft-versus host disease (GVHD). We have undertaken experiments to try to dissociate GVL from GVHD. Transfer of immune spleen cells induced a greater GVL than transfer of normal spleen cells with an equivalent to GVHD. Three to five million immune or normal CD8+ T lymphocytes were sufficient to induce both GVL and GVHD. Individual DBA/2 mice were labeled and followed. In mice undergoing GVHD, the spleens were repopulated by donor (H-2b) lymphocytes, and tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) were present in the sera of 26 of 27 and 18 of 20 mice, respectively, together with increased amounts of TNF-alpha and IL-6 mRNA in their spleens. This was in contrast to DBA/2 mice receiving allogeneic cells but not developing GVHD. Both interferon-alpha/beta (IFN-alpha/beta) and IL-12, which had proven very effective in association with adoptive transfer of syngeneic immune T lymphocytes in inhibiting ESb metastases, enhanced GVHD when administered with allogeneic immune or normal spleen cells, and >90% of mice died. Intensive IL-2 treatment inhibited GVHD while maintaining GVL.
经静脉注射到DBA/2（H-2d）小鼠体内的ESb淋巴瘤细胞在肝脏中迅速增殖，并在几天内杀死所有小鼠。将同种异体C57B1/6（H-2b）肿瘤免疫或正常脾淋巴细胞过继转移到经亚致死剂量照射的DBA/2小鼠中，可诱导显著的抗肿瘤状态，即移植物抗白血病（GVL），使平均存活时间增加2至3倍，但也会诱发急性致死性移植物抗宿主病（GVHD）。我们进行了实验，试图将GVL与GVHD分离。免疫脾细胞的转移比等量正常脾细胞的转移诱导出更强的GVL，但GVHD相当。300万至500万免疫或正常的CD8+T淋巴细胞足以诱导GVL和GVHD。对个体DBA/2小鼠进行标记并跟踪观察。在发生GVHD的小鼠中，脾脏被供体（H-2b）淋巴细胞重新填充，27只小鼠中有26只、20只小鼠中有18只的血清中分别出现肿瘤坏死因子-α（TNF-α）和白细胞介素-6（IL-6），同时其脾脏中TNF-α和IL-6 mRNA的量增加。这与接受同种异体细胞但未发生GVHD的DBA/2小鼠形成对比。干扰素-α/β（IFN-α/β）和IL-12在与同基因免疫T淋巴细胞过继转移联合使用时，已被证明在抑制ESb转移方面非常有效，但与同种异体免疫或正常脾细胞一起给药时会增强GVHD，超过90%的小鼠死亡。强化IL-2治疗可抑制GVHD，同时维持GVL。
