Role of SP-A Gene Polymorphism in Lung Transplantation

描述(申请人提供)：肺移植是一种被广泛接受的终末期肺部疾病的治疗选择。然而，临床结果仍然受到原发移植物衰竭的挑战，移植物衰竭是早期死亡的主要原因，慢性同种异体移植功能障碍和慢性排斥反应占术后第三年后死亡的30%以上。肺移植的受者和移植物5年存活率为50%，明显低于肝、肾和心脏移植(超过70%)。持续的肺部暴露在环境中可能是决定性因素，防御机制的表现起着重要作用。肺表面活性物质蛋白(SP)A、B、C和D是肺可以装载的第一个宿主防御机制之一。尤其是SP-A，是一种由II型肺泡细胞产生的调理素，在天然免疫系统和获得性免疫系统中具有活性，包括调节巨噬细胞和淋巴细胞反应。值得注意的是，SP-A的生物学活性似乎是由基因决定的，并且SP-A基因多态性与各种肺部疾病有关，包括呼吸窘迫综合征、特发性肺纤维化和肺气肿。我们推测，SP-A基因的变异性与移植肺对移植相关有害事件的不同耐受性有关。SP-A的两个基因SP-A1和SP-A2在编码区SP-A1(6A，6A2-20)和SP-A2(1A，1A0-13)具有多个多态性。在对我们的假设进行的初步研究中，供体肺的SP-A1和SP-A2基因变异与移植后慢性肺功能障碍的生存和发展有关。SP-A2基因1A0-1A2、3、5、9与同种异体肺移植后肺泡灌洗液中SP-A蛋白水平及植入时肺组织中SP-A mRNA水平降低相关。此外，移植后30天内死亡的患者在移植时肺组织中SP-AMR NA水平显著降低。从一小群患者中获得的这些初步发现表明了一种新的范例，即由基因决定的SP-A功能有助于同种异体移植的功能和存活。我们建议在一项适当有力的研究中评估SP-A基因多态性是否可以预测原发性移植物功能障碍和/或慢性肺移植物功能障碍，以及这些基因多态性是否可以作为肺移植物功能障碍的生物标志物。我们还建议研究免疫抑制药物和SP-A表达之间的相互作用，并确定这是否依赖于SP-A变体。体外研究表明，肺移植中的主要免疫抑制药物之一类固醇对SP-A的表达有不同的影响。这一建议将产生新的信息，提高我们对同种异体肺移植功能障碍的理解。可以想象，所获得的信息将激发多中心研究的兴趣，以调查SP-A基因多态性是否可以整合到供体肺选择标准中和/或实施移植后定制免疫抑制。 公共卫生相关性：迄今为止，与肺移植相关的研究主要集中在与受体相关的免疫生物学上，就像其他固体器官移植研究一样。这项提案将侧重于供者的先天免疫，并将研究表面活性蛋白A作为肺移植器官特异性先天免疫的关键分子。表面活性蛋白A将作为肺移植功能障碍的预测和生物标记物，在遗传学和蛋白质水平上进行研究。这项研究将加深我们对同种异体肺移植功能障碍的认识，这是肺移植长期成功的主要限制因素。

DESCRIPTION (provided by applicant): Lung transplantation is a widely accepted therapeutic option for end stage lung disease. However, clinical outcomes are yet challenged by primary graft failure, which is responsible for the majority of early mortality, and by chronic allograft dysfunction and chronic rejection, accounting for more than 30% of deaths after the third postoperative year. Lung transplantation offers a 50% recipient and graft 5-yr survival, which is significantly lower than for liver, kidney, and heart transplantation (over 70%). The ongoing lung's exposure to the environment is likely the determining factor, with a significant role being played by the performance of the defense mechanisms. Pulmonary surfactant proteins (SP) A, B, C, and D are one of the first host defense mechanisms the lung can mount. SP-A in particular, is an opsonin produced by the type II pneumocytes, and is active in the innate and adaptive immune system including regulating macrophage and lymphocyte responses. Of note, SP-A biologic activity seems to be genetically determined, and SP-A polymorphisms have been associated with various lung diseases including respiratory distress syndrome, idiopathic pulmonary fibrosis, and emphysema. We hypothesize that SP-A gene variability is responsible for the different tolerance of lung grafts to transplant-related noxious events. The two SP-A genes SP-A1 and SP-A2 have several polymorphisms within the coding region, SP-A1 (6A, 6A2- 20), and SP-A2 (1A, 1A0-13). In preliminary studies performed to test our hypothesis, donor lung SP-A1 and SP- A2 genetic variants were associated with survival and development of chronic lung dysfunction following transplantation. SP-A2 genotypes 1A0-1A2,3,5,9, were correlated with lower levels of SP-A mRNA within allografts at implantation and lower SP-A protein levels in the broncho-alveolar lavage fluid post transplantation. Moreover, patients who died within 30 days of transplantation had significantly lower levels of SP-A mRNA in their lung allografts at implantation. These preliminary findings obtained from a small cohort of patients suggest a new paradigm where genetically determined SP-A function contributes to allograft function and survival. We are proposing to evaluate, in an appropriately powered study, if SP-A gene polymorphisms predict primary graft dysfunction and/or chronic lung graft dysfunction, and if these polymorphisms could serve as biomarkers of lung graft dysfunction. We also propose to study the interaction between immunosuppressive drugs and SP- A expression and determine whether this is dependent on SP-A variants. In vitro studies have shown variable SP-A expression in response to steroids, one of the primary immunosuppressive drugs in lung transplantation. This proposal will generate novel information improving our understanding of lung allograft dysfunction. It is conceivable that the information obtained will stimulate the interest for a multi centre study to investigate if SP- A polymorphism may be integrated in the donor lung selection criteria and/or to implement post transplant tailored immunosuppression. PUBLIC HEALTH RELEVANCE: Lung transplantation related research has to date predominantly focused on recipient related immune biology, as done for other solid organ transplant research. This proposal will focus on donor innate immunity and will study surfactant protein A as a key molecule in the lung allograft organ specific, innate immunity. Surfactant protein A will be studied both at a genetic and protein level as a predictor and biomarker of lung allograft dysfunction. This study will increase our understanding of lung allograft dysfunction which is the major limiting factor for the long term success of lung transplantation.