AMELIORATION OF THE DELETERIOUS EFFECTS OF DONOR BRAIN DEATH

改善供体脑死亡的有害影响

基本信息

批准号：
8724980
负责人：
Maria Lucia Madariaga
金额：
$ 5.4万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-06 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8724980
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

项目摘要

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）：终末期肺部疾病患者肺移植的成功受到了慢性排斥的高发病率的限制，慢性排斥反应的发生率很高，仅通过使用免疫抑制药物来部分改善。但是，在许多临床前研究中，我们观察到移植耐受性的诱导可以防止急性和慢性排斥，并消除了对长期免疫抑制的需求，这在患者中通常会导致机会性感染，毒性和恶性肿瘤。当在理想的实验室条件下移植时，我们的中心已经证明了在接受完全不匹配的肺同种异体移植的猪（健康麻醉供体中具有最小缺血时代的健康麻醉供体）时诱导耐受性的能力。但是，当从脑死亡的肺供体（这是常见的临床情况）中采购相同的肺时，耐受性就会消除。我们假设与供体脑死亡相关的炎症状态阻止了这种临床前模型中的耐受性。我们的长期目标是制定策略，以最大程度地减少促炎状态对供体移植的负面影响。在此提案中，我们将确定1）在植入之前对供体移植物的特定炎症途径的阻塞或2）在植入之前对供体移植物进行了治疗，将恢复从脑死亡供体中获得的移植物的耐受性。具体而言，我们将使用抗体来阻断炎症细胞因子IL-6和IL1，并用稳定的灌注液灌注供体移植物。我们的结果将发现潜在的策略为了最大化耐受性诱导，这将在临床上适用于接受肺部肺部疾病的肺移植的患者。我们中心的研究培训计划非常适合将年轻的研究人员发展成为独立科学家。这是通过全面的培训课程来完成的，包括受监督的实验工作，教学教学和技术培训。我们中心的研究员参与研究的各个方面，包括实验计划，设计以及数据分析和解释。我们的研究员也有足够的机会与移植免疫学领域的许多世界一流的能力互动。