Role of CXCL9/CXCR3 chemokine biology during pathogenesis of acute lung allograft rejection
Role of CXCL9/CXCR3 chemokine biology during pathogenesis of acute lung allograft rejection
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DOI：
10.4049/jimmunol.171.9.4844
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发表时间：
2003-11-01
影响因子：
4.4
通讯作者：
Strieter, RM
中科院分区：
文献类型：
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作者：
Belperio, JA;Keane, MP;Strieter, RM
急性同种异体移植排斥是肺移植后的主要并发症，也是闭塞性细支气管炎综合征发生的主要危险因素。急性排斥的特征是移植物内活化的单核细胞浸润。 ELR 阴性 CXC 趋化因子 CXCL9、CXCL10 和 CXCL11 是单核细胞的有效趋化剂，并通过其共享受体 CXCR3 发挥作用。支气管肺泡灌洗液中这些趋化因子水平升高与人类急性肺同种异体移植排斥有关。这导致了这样的假设：同种异体反应期间这些趋化因子的表达促进单核细胞的募集，导致急性肺同种异体移植排斥。我们在急性排斥反应的大鼠原位肺移植模型中进行了研究，发现 CXCL9 和 CXCL10 的表达增加，同时将单核细胞和表达 CXCR3 的细胞募集到同种异体移植物中。然而，在最大排斥期间，CXCL9 水平比 CXCL10 高 15 倍。抑制 CXCL9 会减少移植物内单核细胞的募集和 CXCR3 的细胞表达，从而降低急性肺同种异体移植物排斥评分。此外，低剂量环孢菌素 A 与抗 CXCL9 治疗的组合对移植物内白细胞浸润和降低急性同种异体移植物排斥评分具有更深远的影响。这支持了这样的观点，即CXCL9与表达CXCR3的细胞相互作用在单核细胞的募集中具有重要作用，而单核细胞是急性肺同种异体移植排斥的发病机制中的关键事件。
Acute allograft rejection is a major complication postlung transplantation and is the main risk factor for the development of bronchiolitis obliterans syndrome. Acute rejection is characterized by intragraft infiltration of activated mononuclear cells. The ELR-negative CXC chemokines CXCL9, CXCL10, and CXCL11) are potent chemoattractants for mononuclear cells and act through their shared receptor, CXCR3. Elevated levels of these chemokines in bronchoalveolar lavage fluid have been associated with human acute lung allograft rejection. This led to the hypothesis that the expression of these chemokines during an allogeneic response promotes the recruitment of mononuclear cells, leading to acute lung allograft rejection. We performed studies in a rat orthotopic lung transplantation model of acute rejection, and demonstrated increased expression of CXCL9 and CXCL10 paralleling the recruitment of mononuclear cells and cells expressing CXCR3 to the allograft. However, CXCL9 levels were 15-fold greater than CXCL10 during maximal rejection. Inhibition of CXCL9 decreased intragraft recruitment of mononuclear cells and cellular expression of CXCR3, resulting in lower acute lung allograft rejection scores. Furthermore, the combination of low dose cyclosporin A with anti-CXCL9 therapy had more profound effects on intragraft leukocyte infiltration and in reducing acute allograft rejection scores. This supports the notion that CXCL9 interaction with cells expressing CXCR3 has an important role in the recruitment of mononuclear cells, a pivotal event in the pathogenesis of acute lung allograft rejection.