AMELIORATION OF THE DELETERIOUS EFFECTS OF DONOR BRAIN DEATH

描述（由申请人提供）：肺移植在终末期肺病患者中的成功受到慢性排斥反应高发生率的限制，使用免疫抑制药物只能部分改善。然而，在许多临床前研究中，我们观察到移植耐受的诱导可以预防急性和慢性排斥反应，并消除对长期免疫抑制的需要，长期免疫抑制在患者中通常会导致机会性感染，毒性和恶性肿瘤。 我们的中心已经证明了在理想的实验室条件下（健康的麻醉供体，缺血时间最短），在接受完全不匹配的肺同种异体移植物的猪中诱导耐受的能力。然而，当同样的肺从脑死亡的肺供体获得时（这是常见的临床情况），耐受性被废除。我们假设与供体脑死亡相关的炎症状态阻止了该临床前模型中耐受的诱导。我们的长期目标是制定策略，以尽量减少促炎状态对供体移植物的负面影响。 在本提案中，我们将确定1）特异性炎症通路的阻断或2）植入前供体移植物的离体处理是否会恢复从脑死亡供体获得的移植物的耐受性。 具体来说，我们将使用抗体来阻断炎性细胞因子IL-6和IL-1，并用稳定的灌注液离体灌注供体移植物。我们的研究结果将揭示潜在的战略 以最大限度地诱导耐受，这将在临床上适用于接受肺移植治疗终末期肺病的患者。 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。这是通过一个全面的培训课程，包括监督实验工作，教学指导和技术培训。我们中心的研究员参与研究的各个方面，包括实验规划和设计以及数据分析和解释。我们的研究员还有充分的机会向移植免疫学领域的许多世界一流学院进行演讲并与之互动。

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.