AMELIORATION OF THE DELETERIOUS EFFECTS OF DONOR BRAIN DEATH

改善供体脑死亡的有害影响

• 批准号: 8457430
• 负责人: Maria Lucia Madariaga
• 金额: $ 5.57万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-06 至 2015-08-05
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8457430
• 关键词: Acute; Antibodies; Biopsy; Brain Death; Chronic; Clinical; Data; Data Analyses; Educational Curriculum; Faculty; Family suidae; Gene Expression; Graft Tolerance; Harvest; Immunology; Immunosuppression; Immunosuppressive Agents; Implant; Incidence; Inflammation; Inflammatory; Instruction; Interleukin-1; Interleukin-6; Laboratories; Life Expectancy; Lung; Lung Transplantation; Lung diseases; Malignant Neoplasms; Measures; Miniature Swine; Modeling; National Research Service Awards; Opportunistic Infections; Pathway interactions; Patients; Pharmaceutical Preparations; Pre-Clinical Model; Research; Research Personnel; Research Training; Resuscitation; Scientist; Serum; Staging; T-Cell Activation; Techniques; Time; Toxic effect; Training; Training Programs; Transplant Recipients; Transplantation; Work; clinical practice; cytokine; design; ex vivo perfusion; immune activation; implantation; inflammatory marker; lung allograft; preclinical study; prevent; public health relevance; success

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.

描述（由申请人提供）：终末期肺病患者肺移植的成功受到慢性排斥反应高发生率的限制，而使用免疫抑制药物只能部分改善这种排斥反应。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，并消除长期免疫抑制的需要，长期免疫抑制通常会导致患者机会性感染、毒性和恶性肿瘤。 我们的中心已经证明，在理想的实验室条件下（健康麻醉的供体，缺血时间最短）移植时，能够诱导接受完全不匹配的同种异体肺移植物的猪产生耐受性。然而，当从脑死亡的肺捐赠者那里获得相同的肺时（这是常见的临床情况），耐受性就会被消除。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性的诱导。我们的长期目标是制定策略，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) 阻断特定炎症途径或 2) 在植入前对供体移植物进行离体治疗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症细胞因子 IL-6 和 IL1，并用稳定灌注液离体灌注供体移植物。我们的结果将揭示潜在的策略 最大限度地提高耐受性诱导，这将适用于因终末期肺病而接受肺移植的患者。 我们中心的研究培训计划非常适合将年轻研究人员培养成独立科学家。这是通过全面的培训课程来实现的，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各个方面的研究，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足的机会向移植免疫学领域的许多世界一流院系进行展示并与之互动。