Thalidomide and immunomodulatory derivatives augment natural killer cell cytotoxicity in multiple myeloma
Thalidomide and immunomodulatory derivatives augment natural killer cell cytotoxicity in multiple myeloma
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DOI：
10.1182/blood.v98.1.210
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发表时间：
2001-07-01
期刊：
影响因子：
20.3
通讯作者：
Anderson, KC
中科院分区：
文献类型：
--
作者：
Davies, FE;Raje, N;Anderson, KC
沙利度胺（塔尔）的抗血管生成活性，加上多发性骨髓瘤（MM）骨髓血管生成的增加，提供了在MM中使用That的基本原理。以前，That及其类似物（免疫调节药物，IMiDs）对MM细胞的直接抗MM活性被证明，表明多种作用机制。在本研究中，检查了塔尔/lMiD在MM中的潜在免疫调节作用。已经证明，塔尔/lMiD不单独诱导T细胞增殖，而是作为共刺激因子触发MM患者的抗CD 5刺激的T细胞增殖，伴随干扰素-γ和IL-2分泌的增加。然而，不能证明患者MM细胞的自体T细胞杀伤增加。由于用塔尔/IMiD处理的IL-2致敏的外周血单核细胞（PBMC）显示出对MM细胞系的溶解显着增加，因此表明自然杀伤（NK）和LAK细胞介导的杀伤作用。冷靶点抑制试验表明NK细胞介导的杀伤作用大于LAK细胞介导的杀伤作用。此外，这种杀伤作用不受主要组织相容性复合物类别的限制，并且CD 56（+）细胞的消耗阻断了药物诱导的MM细胞溶解。还观察到用塔尔/lMiD处理的自体PBMC对患者MM细胞的杀伤增加，这是显著的。尽管NK细胞介导的MM细胞杀伤的体内相关性尚不清楚，但在接受塔尔治疗的MM患者中进行的表型分析表明，对治疗有反应的患者中CD 3（-）CD 56（+）细胞增加。因此，体外和体内数据支持这一假设，即That可能至少部分通过调节NK细胞数量和功能介导其抗MM作用。(C)2001年，美国血液学会。
The antiangiogenic activity of thalidomide (Thal), coupled with an,increase In bone marrow angiogenesis in multiple myeloma (MM), provided the rationale for the use of That in MM. Previously, the direct anti-MM activity of That and its analogues (immunomodulatory drugs, IMiDs) on MM cells was demonstrated, suggesting multiple mechanisms of action. In this study, the potential immuno-modulatory effects of Thal/lMiDs in MM were examined. It was demonstrated that Thal/lMiDs do not induce T-cell proliferation alone but act as costimulators to trigger proliferation of anti-CD5-stimulated T cells from patients with MM, accompanied by an increase in interferon-gamma and IL-2 secretion. However, an increase in autologous T-cell killing of patient MM cells could not be demonstrated. A role for natural killer (NK)- and LAK-cell-mediated killing is suggested because IL-2-primed peripheral blood mononuclear cells (PBMCs) treated with Thal/ IMiDs demonstrated significantly increased lysis of MM cell lines. Cold target inhibition assays suggested NK- rather than LAK-cell-mediated killing. Furthermore, this killing was not major histocompatibility complex-class restricted, and the depletion of CD56(+) cells blocked the drug-induced MM cell lysis, It was significant that increased killing of patient MM cells by autologous PBMCs treated with Thal/lMiDs Was also observed. Although the in vivo relevance of NK-cell-mediated MM cell killing is unknown, phenotypic analysis performed in MM patients receiving Thal therapy demonstrated an increase in CD3(-)CD56(+) cells in patients responding to therapy. Thus in vitro and in vivo data support the hypothesis that That may mediate its anti-MM effect, at least in part, by modulating NK cell number and function. (C) 2001 by The American Society of Hematology.