Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
T. Tsao and L. Qiu contributed equally.
Eur Respir J. 2024 Sep 26;64(3). doi: 10.1183/13993003.02171-2023. Print 2024 Sep.
Pulmonary ischaemia-reperfusion injury (IRI) is a major contributor to poor lung transplant outcomes. We recently demonstrated a central role of airway-centred natural killer (NK) cells in mediating IRI; however, there are no existing effective therapies for directly targeting NK cells in humans.
We hypothesised that a depleting anti-CD94 monoclonal antibody (mAb) would provide therapeutic benefit in mouse and human models of IRI based on high levels of (CD94) transcripts in bronchoalveolar lavage samples from lung transplant patients.
We found that CD94 is highly expressed on mouse and human NK cells, with increased expression during IRI. Anti-mouse and anti-human mAbs against CD94 showed effective NK cell depletion in mouse and human models and blunted lung damage and airway epithelial killing, respectively. In two different allogeneic orthotopic lung transplant mouse models, anti-CD94 treatment during induction reduced early lung injury and chronic inflammation relative to control therapies. Anti-CD94 did not increase donor antigen-presenting cells that could alter long-term graft acceptance.
Lung transplant induction regimens incorporating anti-CD94 treatment may safely improve early clinical outcomes.
肺缺血再灌注损伤（IRI）是导致肺移植不良结局的主要原因。我们最近证明了气道中心自然杀伤（NK）细胞在介导 IRI 中的核心作用；然而，目前尚无针对人类 NK 细胞的有效治疗方法。
我们假设，基于肺移植患者支气管肺泡灌洗液样本中高表达（CD94）转录本，耗竭抗 CD94 单克隆抗体（mAb）将在 IRI 的小鼠和人类模型中提供治疗益处。
我们发现 CD94 在小鼠和人类 NK 细胞上高度表达，在 IRI 期间表达增加。针对小鼠和人类的抗 CD94 mAb 可有效耗竭 NK 细胞，并分别减轻肺损伤和气道上皮细胞杀伤。在两种不同的同种异体原位肺移植小鼠模型中，与对照治疗相比，诱导期的抗 CD94 治疗可减少早期肺损伤和慢性炎症。抗 CD94 治疗不会增加改变长期移植物接受的供体抗原呈递细胞。
包含抗 CD94 治疗的肺移植诱导方案可能安全地改善早期临床结果。
