Adenosine 2A Receptor Signaling in Lung Transplant Injury and Rejection

描述(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发挥了作用。抗炎Gs偶联的腺苷A2a受体(A2AR)激动剂已被证明能抑制大多数炎症细胞的活性，并且有广泛的临床前证据表明它们可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。在BO的病因中，有证据支持同种免疫依赖和同种免疫非依赖因素。最近，淋巴细胞和抗原提呈细胞上A2AR的激活被证明可以减弱同种异体免疫反应。此外，淋巴细胞上A2AR的刺激和上调通过诱导T细胞无能来促进外周耐受。目前对A2AR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，A2AR信号在调节与BO发病相关的先天和获得性免疫反应中起关键作用。目的1：利用活体肺IRI模型，确定NKT细胞上的A2AR信号是否对肺IRI具有保护作用。目的2：利用非血运重建的异位气管模型和转基因小鼠品系，确定A2AR信号在BO发病机制中的重要性和细胞机制。目的3：将确定A2AR信号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标准免疫抑制方案的A2AR激动剂。这笔赠款包括为PI提供的培训计划，其中包括课程作业以及与导师和顾问的频繁互动。在候选人顾问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人员所需的技能。相关性(见说明书)：BO仍然是肺移植受者长期存活的主要障碍。目前还没有统一一致的战略来预防/治疗BO。IRI是BO的重要危险因素。鉴于A2AR的抗炎和免疫调节作用，利用A2AR激动剂的策略可能是唯一适合于预防BO中涉及的同种免疫非依赖性和同种免疫依赖性因子的策略。

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.