Adenosine 2A Receptor Signaling in Lung Transplant Injury and Rejection

描述（由申请人提供）：肺缺血再灌注损伤（IRI）的发病机制历来以中性粒细胞的募集和外渗为特征。然而，最近的研究表明，自然杀伤T细胞（NKT）在这种损伤的发病机制中起作用。抗炎性GS-偶联腺苷A2 A受体（A2 AR）的激动剂已显示出抑制大多数炎性细胞的活性，并且存在广泛的临床前证据表明其用于预防急性缺血再灌注。重要的是，IRI是发生慢性同种异体移植排斥反应、闭塞性细支气管炎（BO）的重要危险因素。证据支持同种免疫依赖性和同种免疫无关性因素的病因BO。最近，淋巴细胞和抗原呈递细胞上A2 AR的活化已显示减弱同种免疫应答。此外，A2 AR刺激和淋巴细胞上的上调通过诱导T细胞无反应性来促进外周耐受。目前对A2 AR激动剂在肺移植排斥反应中的作用知之甚少。我们的总体假设是A2 AR信号传导在调节与BO发病机制相关的先天性和适应性免疫应答中是关键的。目标1：将使用体内肺IRI模型确定NKT细胞上特异性的A2 AR信号传导是否能提供肺IRI的保护。目标二：将使用非血管重建异位气管模型和基因修饰小鼠品系确定A2 AR信号传导在BO发病机制中的重要性和细胞机制。目的3：将确定A2 AR信号传导是否可用于促进耐受状态的发展。还将讨论如何有效地引入A2 AR激动剂与标准的免疫抑制方案。该补助金包括PI的培训计划，其中包括课程以及与导师和顾问的频繁互动。在候选人咨询委员会的指导和弗吉尼亚大学外科系提供的机构支持下，候选人将发展成为独立调查员所需的技能。相关性（见说明）：BO仍然是肺移植受者长期生存的主要障碍。目前还没有统一一致的策略来预防/治疗BO。IRI是BO的重要危险因素。考虑到A2 AR的抗炎和免疫调节作用，利用A2 AR激动剂的策略可能独特地适合于预防BO中涉及的同种免疫非依赖性和同种免疫依赖性因子。

DESCRIPTION (provided by applicant): The pathogenesis of lung ischemia reperfusion injury (IRI) has historically been characterized by the recruitment and extravasation of neutrophils. However, more recent studies have suggested a role for natural killer T-cells (NKT) in the pathogenesis of this injury. Agonists of the anti-inflammatory Gs-coupled adenosine A2A receptor (A2AR) have been shown to inhibit the activity of most inflammatory cells, and extensive preclinical evidence exists for their use in prevention of acute ischemia reperfusion. Importantly, IRI is a significant risk factor for the development of chronic allograft rejection, bronchiolitis obliterans (BO). Evidence supports alloimmune-dependent and alloimmune-independent factors in the etiology BO. More recently activation of A2ARs on lymphocytes and antigen presenting cells have been shown to attenuate the alloimmune response. Additionally A2AR stimulation and upregulation on lymphocytes promotes peripheral tolerance by inducing T-cell anergy. Currently little is known about the role of A2AR agonists in lung transplant rejection. Our overall hypothesis is that A2AR signaling is critical in modulating the innate and adaptive immune responses relevant to the pathogenesis of BO. Aim 1: Will determine, using an in-vivo lung IRI model, if A2AR signaling specifically on NKT cells confers protection from lung IRI. Aim 2: Will determine, using a non-revascularized heterotopic tracheal model and genetically modified mice strains, the importance and cellular mechanisms of A2AR signaling in the pathogenesis of BO. Aim 3: Will determine if A2AR signaling can be used to promote the development of a tolerant state. Also addressed will be ways to effectively introduce A2AR agonists with standard immunosuppression regimens. This grant encompasses a training program for the PI which includes coursework plus frequent interactions with mentors and advisors. With the guidance of the candidate's advisory committee and the institutional support provided by the University of Virginia's Department of Surgery, the candidate will development the skills required to evolve into an independent investigator. RELEVANCE (See instructions): BO remains the major hurdle to long-term survival in lung transplant recipients. There currently are no uniformly consistent strategies to prevent/treat BO. IRI is a significant risk factor for BO. Given the anti- inflammatory and immunomodulating effects of A2ARs, strategies utilizing A2AR agonists may be uniquely suited to prevent both the alloimmune-independent and alloimmune-dependent factors involved in BO.