Graft-versus-host disease is enhanced by extracellular ATP activating P2X7R
Graft-versus-host disease is enhanced by extracellular ATP activating P2X7R
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DOI：
10.1038/nm.2242
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发表时间：
2010-12-01
期刊：
影响因子：
82.9
通讯作者：
Zeiser, Robert
中科院分区：
文献类型：
--
作者：
Wilhelm, Konrad;Ganesan, Jayanthi;Zeiser, Robert
细胞损伤时释放的危险信号可导致过度的免疫介导的组织破坏，如急性移植物抗宿主病(GVHD)、同种异体移植排斥反应和全身炎症反应综合征。由于在生理条件下(1)，ATP在胞外间隙中被发现有少量的浓度，其受体P2X(7)R在几种类型的免疫细胞上表达，当ATP从死亡的细胞中释放出来时，可能起到危险信号的作用。我们观察到全身照射后腹腔液中的ATP浓度升高，在小鼠和人类GVHD的发展过程中也是如此。用三磷酸腺苷刺激抗原提呈细胞(APC)后，CD80和CD86在体内外的表达增加，并引发一系列促炎事件，包括信号转导和转录激活因子-1(STAT1)的磷酸化、干扰素-γ的产生和供体T细胞的增殖，而调节性T细胞的数量则减少。随着GVHD的进展，P2X(7)R的表达增加，使APC对ATP的不利影响更有反应，从而提供积极的反馈信号。在GVHD发育过程中，ATP中和、早期P2X(7)R阻断或P2X(7)R的遗传缺陷可提高存活率，而不会出现免疫瘫痪。这些数据对移植医学具有重大意义，因为对通过P2X(7)R作用的危险信号的药理学干扰可能导致在不需要强化免疫抑制的情况下产生耐受性。
Danger signals released upon cell damage can cause excessive immune-mediated tissue destruction such as that found in acute graft-versus-host disease (GVHD), allograft rejection and systemic inflammatory response syndrome. Given that ATP is found in small concentrations in the extracellular space under physiological conditions(1), and its receptor P2X(7)R is expressed on several immune cell types, ATP could function as a danger signal when released from dying cells. We observed increased ATP concentrations in the peritoneal fluid after total body irradiation, and during the development of GVHD in mice and in humans. Stimulation of antigen-presenting cells (APCs) with ATP led to increased expression of CD80 and CD86 in vitro and in vivo and actuated a cascade of proinflammatory events, including signal transducer and activator of transcription-1 (STAT1) phosphorylation, interferon-gamma (IFN-gamma) production and donor T cell expansion, whereas regulatory T cell numbers were reduced. P2X(7)R expression increased when GVHD evolved, rendering APCs more responsive to the detrimental effects of ATP, thereby providing positive feedback signals. ATP neutralization, early P2X(7)R blockade or genetic deficiency of P2X(7)R during GVHD development improved survival without immune paralysis. These data have major implications for transplantation medicine, as pharmacological interference with danger signals that act via P2X(7)R could lead to the development of tolerance without the need for intensive immunosuppression.