AMELIORATION OF THE DELETERIOUS EFFECTS OF DONOR BRAIN DEATH

描述(申请人提供)：慢性排斥反应的高发生率限制了终末期肺部疾病患者肺移植的成功，而免疫抑制药物的使用只能部分改善慢性排斥反应。然而，在许多临床前研究中，我们观察到，诱导移植耐受可以防止急性和慢性排斥反应，并消除长期免疫抑制的需要，而长期免疫抑制往往会导致机会性感染、毒性和恶性。我们的中心已经证明，在理想的实验室条件下(健康的麻醉供体，缺血时间最短)，接受完全不相合的同种异体肺移植的猪能够诱导耐受。然而，当相同的肺是从脑死亡的肺捐赠者那里获得的(这是常见的临床场景)，耐受性被废除。我们假设，在这个临床前模型中，与供体脑死亡相关的炎症状态阻止了耐受性的诱导。我们的长期目标是制定策略，将促炎状态对供体移植物的负面影响降至最低。在这项建议中，我们将确定是否1)阻断特定的炎症通路或2)在植入前对供者移植物进行体外治疗，以恢复从脑死亡供者获取的移植物的耐受性。 具体地说，我们将使用抗体来阻断炎性细胞因子IL-6和IL-1，并在体外用稳定的灌流液灌流供体移植物。我们的结果将揭示潜在的战略 最大限度地诱导耐受性，这将在临床上适用于终末期肺部疾病接受肺移植的患者。我们中心的研究培训计划非常适合将年轻的研究人员培养成独立的科学家。这是通过全面的培训课程来实现的，包括有监督的实验工作、教学指导和技术培训。我们中心的研究员参与研究的方方面面，包括实验规划和设计以及数据分析和解释。我们的研究员也有足够的机会向移植免疫学领域的许多世界级院系发表演讲并与之互动。

DESCRIPTION (provided by applicant): The success of lung transplantation in patients with end-stage lung disease has been limited by a high incidence of chronic rejection, which has only been partially ameliorated by the use of immunosuppressive drugs. However, in many preclinical studies, we have observed that the induction of transplant tolerance prevents acute and chronic rejection, and eliminates the need for long-term immunosuppression, which in patients often leads to opportunistic infection, toxicity, and malignancy. Our center has demonstrated the ability to induce tolerance in swine receiving fully mismatched lung allografts, when transplanted under ideal laboratory conditions (healthy anesthetized donors with minimal ischemic times). However, when the same lungs are procured from a brain-dead lung donor (which is the common clinical scenario), tolerance is abrogated. We hypothesize that the inflammatory state associated with donor brain death prevents the induction of tolerance in this preclinical model. Our long-term objective is to develop strategies to minimize the negative impact of pro-inflammatory states on the donor graft. In this proposal, we will determine whether 1) the blockade of specific inflammatory pathways or 2) ex vivo treatment of the donor graft prior to implantation will restore tolerogenicity to grafts procured from a brain-dead donor. Specifically, we will use antibodies to block the inflammatory cytokines IL-6 and IL1, and perfuse the donor graft ex vivo with a stabilizing perfusate. Our results will uncover potential strategies to maximize tolerance induction that will be clinically applicable to patients undergoing lung transplantation for end- stage lung disease. The research training program at our center is ideally suited to developing young investigators into independent scientists. This is accomplished through a comprehensive training curriculum including supervised experimental work, didactic instruction, and technical training. Fellows at our center participate in all aspect of research, including experimental planning and design and data analysis and interpretation. Our fellows also have ample opportunities to present to and interact with many world-class faculties in the field of transplant immunology.