Belperio John A, Keane Michael P, Burdick Marie D, Lynch Joseph P, Zisman David A, Xue Ying Ying, Li Kewang, Ardehali Abbas, Ross David J, Strieter Robert M
Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of California School of Medicine, Los Angeles, CA 90095, USA.
J Immunol. 2003 Nov 1;171(9):4844-52. doi: 10.4049/jimmunol.171.9.4844.
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.
急性同种异体移植排斥反应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。急性排斥反应的特征是移植体内活化的单核细胞浸润。ELR阴性的CXC趋化因子（CXCL9、CXCL10和CXCL11）是单核细胞的有效趋化剂，并通过其共同受体CXCR3发挥作用。支气管肺泡灌洗液中这些趋化因子水平的升高与人类急性肺同种异体移植排斥反应相关。这导致了这样一种假说，即在同种异体反应过程中这些趋化因子的表达促进了单核细胞的募集，从而导致急性肺同种异体移植排斥反应。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，结果表明CXCL9和CXCL10的表达增加与单核细胞以及表达CXCR3的细胞向同种异体移植物的募集平行。然而，在最大排斥反应期间，CXCL9的水平比CXCL10高15倍。抑制CXCL9可减少移植体内单核细胞的募集以及CXCR3的细胞表达，从而降低急性肺同种异体移植排斥反应评分。此外，低剂量环孢素A与抗CXCL9疗法联合使用对移植体内白细胞浸润和降低急性同种异体移植排斥反应评分具有更显著的效果。这支持了这样一种观点，即CXCL9与表达CXCR3的细胞之间的相互作用在单核细胞募集中起重要作用，而单核细胞募集是急性肺同种异体移植排斥反应发病机制中的关键事件。
