Ecto-5'-nucleotidase (CD73) attenuates allograft airway rejection through adenosine 2A receptor stimulation.
Ecto-5'-nucleotidase (CD73) attenuates allograft airway rejection through adenosine 2A receptor stimulation.
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DOI：
10.4049/jimmunol.0901847
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发表时间：
2010-07-15
期刊：
影响因子：
--
通讯作者：
Pinsky DJ
中科院分区：
文献类型：
--
作者：
Ohtsuka T;Changelian PS;Bouïs D;Noon K;Harada H;Lama VN;Pinsky DJ
在肺同种异体移植物中有多种白细胞募集的驱动因素，其促成淋巴细胞性支气管炎（LB）和闭塞性细支气管炎（BO）。驱动（或抑制）白细胞运输到同种异体移植物的先天机制仍不完全清楚。本研究验证了CD 73（外-5 ′核苷酸酶），一种催化AMP转化为腺苷的酶，是LB和BO的关键负调节剂的假设。将野生型（WT）小鼠的气管同种异体移植物植入CD 73 −/−受体后，7 d时气道管腔闭塞显著增加（CD 73 −/−和WT同种异体移植物受体分别为62 ± 4%和47 ± 5%; p = 0.046）。CD 3+淋巴细胞浸润也一致增加（CD 73 −/−和WT同种异体移植物受体分别为523 ± 41个细胞和313 ± 43个细胞; p = 0.013）。因为实时PCR显示WT同种异体移植物中腺苷A2 A受体（A2 AR）的mRNA上调为WT同种异体移植物的43倍（p = 0.032），所以进行额外的实验以确定CD 73的保护作用是否是由于腺苷的产生及其对A2 AR的刺激。用A2 AR激动剂治疗WT受体显著减少了CD 3+淋巴细胞浸润和气道管腔闭塞;对CD 73 −/−受体进行类似治疗使其免于LB和气道闭塞。这些数据表明，CD 73通过腺苷生成及其刺激A2 AR起作用，是淋巴细胞募集到气道同种异体移植物中的关键负调节剂。CD 73/腺苷轴可能成为防治BO的新靶点。
There are multiple drivers of leukocyte recruitment in lung allografts that contribute to lymphocytic bronchitis (LB) and bronchiolitis obliterans (BO). The innate mechanisms driving (or inhibiting) leukocyte trafficking to allografts remain incompletely understood. This study tested the hypothesis that CD73 (ecto-5′ nucleotidase), an enzyme that catalyzes the conversion of AMP to adenosine, is a critical negative regulator of LB and BO. Implantation of tracheal allografts from wild type (WT) mice into CD73−/− recipients revealed a striking increase in airway luminal obliteration at 7 d (62 ± 4% and 47 ± 5% for CD73−/− and WT allograft recipients, respectively; p = 0.046). There was also a concordant increase in CD3+ lymphocytic infiltration (523 ± 41 cells and 313 ± 43 cells for CD73−/− and WT allograft recipients, respectively; p = 0.013). Because real-time PCR revealed a 43-fold upregulation of mRNA for the adenosine A2A receptor (A2AR) in WT allografts compared with WT isografts (p = 0.032), additional experiments were performed to determine whether the protective effect of CD73 was due to generation of adenosine and its stimulation of the A2AR. Treatment of WT recipients with an A2AR agonist significantly reduced CD3+ lymphocyte infiltration and airway luminal obliteration; similar treatment of CD73−/− recipients rescued them from LB and airway obliteration. These data implicate CD73 acting through adenosine generation and its stimulation of the A2AR as a critical negative modulator of lymphocyte recruitment into airway allografts. The CD73/adenosine axis might be a new therapeutic target to prevent BO.
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