Tasha Tsao, Longhui Qiu, Reena Bharti, Avishai Shemesh, Alberto M Hernandez, Simon J Cleary, Nancy Y Greenland, Jesse Santos, Ruoshi Shi, Lu Bai, Jennifer Richardson, Kimberley Dilley, Matthias Will, Nenad Tomasevic, Tereza Sputova, Adam Salles, Jeffrey Kang, Dongliang Zhang, Steven R Hays, Jasleen Kukreja, Jonathan P Singer, Lewis L Lanier, Mark R Looney, John R Greenland, Daniel R Calabrese
{"title":"CD94+ 自然杀伤细胞可增强肺缺血再灌注损伤。","authors":"Tasha Tsao, Longhui Qiu, Reena Bharti, Avishai Shemesh, Alberto M Hernandez, Simon J Cleary, Nancy Y Greenland, Jesse Santos, Ruoshi Shi, Lu Bai, Jennifer Richardson, Kimberley Dilley, Matthias Will, Nenad Tomasevic, Tereza Sputova, Adam Salles, Jeffrey Kang, Dongliang Zhang, Steven R Hays, Jasleen Kukreja, Jonathan P Singer, Lewis L Lanier, Mark R Looney, John R Greenland, Daniel R Calabrese","doi":"10.1183/13993003.02171-2023","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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 <i>KLRD1</i> (CD94) transcripts in bronchoalveolar lavage samples from lung transplant patients.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>Lung transplant induction regimens incorporating anti-CD94 treatment may safely improve early clinical outcomes.</p>","PeriodicalId":12265,"journal":{"name":"European Respiratory Journal","volume":" ","pages":""},"PeriodicalIF":16.6000,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"CD94<sup>+</sup> natural killer cells potentiate pulmonary ischaemia-reperfusion injury.\",\"authors\":\"Tasha Tsao, Longhui Qiu, Reena Bharti, Avishai Shemesh, Alberto M Hernandez, Simon J Cleary, Nancy Y Greenland, Jesse Santos, Ruoshi Shi, Lu Bai, Jennifer Richardson, Kimberley Dilley, Matthias Will, Nenad Tomasevic, Tereza Sputova, Adam Salles, Jeffrey Kang, Dongliang Zhang, Steven R Hays, Jasleen Kukreja, Jonathan P Singer, Lewis L Lanier, Mark R Looney, John R Greenland, Daniel R Calabrese\",\"doi\":\"10.1183/13993003.02171-2023\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Pulmonary ischaemia-reperfusion injury (IRI) is a major contributor to poor lung transplant outcomes. 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引用次数: 0
摘要
肺缺血再灌注损伤（IRI）是导致肺移植效果不佳的主要原因。我们最近证明了以气道为中心的 NK 细胞在介导 IRI 中的核心作用；然而，目前还没有直接针对 NK 细胞的有效疗法。基于肺移植患者支气管肺泡灌洗液样本中高水平的 KLRD1（CD94）转录本，我们假设消耗性抗 CD94 单克隆抗体（mAb）将为小鼠和人类 IRI 模型提供治疗益处。我们发现 CD94 在小鼠和人类 NK 细胞上高度表达，在 IRI 期间表达量增加。针对 CD94 的抗小鼠和抗人 mAbs 在小鼠和人体模型中显示出有效的 NK 细胞耗竭作用，并减缓了肺损伤和气道上皮细胞杀伤。在两种不同的异体正位肺移植小鼠模型中，与对照疗法相比，诱导期间的抗 CD94 治疗可减少早期肺损伤和慢性炎症。抗CD94不会增加供体抗原递呈细胞，从而改变长期移植的接受程度。采用抗CD94治疗的肺移植诱导方案可安全地改善早期临床结果。
Background: 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.
Methods: 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 KLRD1 (CD94) transcripts in bronchoalveolar lavage samples from lung transplant patients.
Results: 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.
Conclusions: Lung transplant induction regimens incorporating anti-CD94 treatment may safely improve early clinical outcomes.
期刊介绍：
The European Respiratory Journal (ERJ) is the flagship journal of the European Respiratory Society. It has a current impact factor of 24.9. The journal covers various aspects of adult and paediatric respiratory medicine, including cell biology, epidemiology, immunology, oncology, pathophysiology, imaging, occupational medicine, intensive care, sleep medicine, and thoracic surgery. In addition to original research material, the ERJ publishes editorial commentaries, reviews, short research letters, and correspondence to the editor. The articles are published continuously and collected into 12 monthly issues in two volumes per year.
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