Botzler C, Ellwart J, Günther W, Eissner G, Multhoff G
GSF-Institute of Molecular Immunology, Munich, Germany.
Exp Hematol. 1999 Mar;27(3):470-8. doi: 10.1016/s0301-472x(98)00055-1.
We previously reported that cell surface expression of hsp70, the major stress inducible member of the 70-kDa heat shock protein family, is inducible by nonlethal heat as well as by treatment with the membrane-interactive compound alkyl-lysophospholipid 1-octadecyl-2-methyl-rac-glycero-3-phosphocholine (ET-18-OCH3) selectively on human tumor cell lines. Plasma membrane expression of hsp70 increases selectively the sensitivity of tumor cells to lysis and, therefore, might play an important role in the antitumor immune response. Here, we demonstrate that a combined treatment consisting of sublethal heat (41.8 degrees C) and a noncytotoxic concentration of ET-18-OCH3 (25 micrograms/mL) results in a synergistic increase in the amount of cell membrane-bound hsp70 on leukemic K562 cells and on freshly isolated bone marrow of a chronic myelogeneous leukemia (CML) patient, but not on peripheral blood lymphocytes or CD34+ hematopoietic progenitor cells of healthy human individuals. Under these conditions the repopulating capacity of progenitor cells was not influenced. The increased hsp70 membrane expression on leukemic K562 cells results in a significantly increased sensitivity to lysis mediated by natural killer cells. In contrast to leukemic cells, the lysis of peripheral blood lymphocytes and CD34+ progenitor cells that lack expression of hsp70 on their plasma membrane was not negatively influenced by this treatment. A nonspecific disruption of the plasma membrane could be excluded, because treatment with a nontoxic concentration of the detergent Tween20 did not have an influence on hsp70 cell surface expression or on the sensitivity to lysis. Our findings might have further clinical implications with respect to purging of bone marrow from patients suffering from leukemia at sublethal conditions to induce a tumor-selective immune response.
我们之前报道过，70 kDa热休克蛋白家族中主要的应激诱导成员hsp70的细胞表面表达可由非致死性热以及用膜相互作用化合物烷基溶血磷脂1-十八烷基-2-甲基-rac-甘油-3-磷酸胆碱（ET-18-OCH3）处理选择性地诱导，且仅在人肿瘤细胞系中出现。hsp70的质膜表达选择性地增加了肿瘤细胞对裂解的敏感性，因此可能在抗肿瘤免疫反应中发挥重要作用。在此，我们证明，由亚致死性热（41.8摄氏度）和非细胞毒性浓度的ET-18-OCH3（25微克/毫升）组成的联合处理导致白血病K562细胞以及一名慢性髓性白血病（CML）患者的新鲜分离骨髓中细胞膜结合的hsp70量协同增加，但对健康个体的外周血淋巴细胞或CD34 +造血祖细胞没有影响。在这些条件下，祖细胞的再增殖能力不受影响。白血病K562细胞上hsp70膜表达的增加导致对自然杀伤细胞介导的裂解敏感性显著增加。与白血病细胞相反，这种处理对外周血淋巴细胞和质膜上缺乏hsp70表达的CD34 +祖细胞的裂解没有负面影响。可以排除质膜的非特异性破坏，因为用无毒浓度的去污剂吐温20处理对hsp70细胞表面表达或对裂解敏感性没有影响。我们的发现对于在亚致死条件下清除白血病患者骨髓以诱导肿瘤选择性免疫反应可能具有进一步的临床意义。
