In vivo p53 response and immune reaction underlie highly effective low-dose radiotherapy in follicular lymphoma
In vivo p53 response and immune reaction underlie highly effective low-dose radiotherapy in follicular lymphoma
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DOI：
10.1182/blood-2007-01-067579
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发表时间：
2007-08-15
期刊：
影响因子：
20.3
通讯作者：
de Jong, Daphne
中科院分区：
文献类型：
--
作者：
Knoops, Laurent;Haas, Rick;de Jong, Daphne
极低剂量照射（2 x 2 Gy）是一种新的、有效的、安全的局部治疗滤泡性淋巴瘤的方法。为了了解这种极端有效反应的生物学机制，我们通过微阵列比较了放疗前后患者活检的基因表达谱。在所有患者中，p53靶基因的主要和一致的诱导被观察到。参与细胞周期阻滞和凋亡的P53靶点表现出相同的调控模式，表明在体内两者是同时被激活的。免疫组织化学证实了P53上调和P53介导的增殖阻滞和凋亡，激活了内源性和外源性凋亡途径。其他诱导基因揭示了一整套与巨噬细胞活化和TH1免疫应答相关的有生物学意义的基因。免疫组织化学分析表明，凋亡细胞特异性激活或分化常驻巨噬细胞。这些生物学见解是主张使用低剂量放疗作为滤泡性淋巴瘤有效姑息治疗的重要论据。此外，本研究首次在患者体内报道了辐射诱导的p53凋亡反应，并表明这种凋亡反应并非免疫沉默。
Very low-dose irradiation (2 x 2 Gy) is a new, effective, and safe local treatment for follicular lymphoma. To understand the biologic mechanisms of this extremely effective response, we compared by microarray the gene-expression profile of patients' biopsies taken before and after radiation. In all patients, a major and consistent induction of p53 target genes was seen. p53 targets involved in cell-cycle arrest and apoptosis showed the same mode of regulation, indicating that, in vivo, both are activated simultaneously. p53 up-regulation and p53-mediated proliferation arrest and apoptosis were substantiated using immunohistochemistry, with activation of both the intrinsic and the extrinsic apoptotic pathways. The other induced genes revealed a whole set of biologically meaningful genes related to macrophage activation and TH1 immune response. Immumohistochemical analysis suggested a specific activation or differentiation of resident macrophages by apoptotic cells. These biologic insights are important arguments to advocate the use of low-dose radiotherapy as an effective palliative treatment for follicular lymphoma. Moreover, this study is the first in vivo report of the radiation-induced p53 apoptotic response in patients and suggests that this apoptotic response is not immunologically silent.