Hepatocyte xenografts for treatment of acute liver failure

肝细胞异种移植治疗急性肝衰竭

• 批准号: 9128195
• 负责人: Ira J. Fox
• 金额: $ 103.4万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-15 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9128195
• 关键词: Acute; Acute Liver Failure; Allografting; Ammonia; Animals; Antigens; Artificial Liver; Biological; Biological Assay; Cells; Clinical; Clinical Medicine; Complex; Devices; Emergency Situation; Evaluation; Experimental Designs; Failure; Family suidae; Functional disorder; Hepatocyte; Hepatocyte transplantation; Human; Image; Immune; Immune response; Immunity; Immunosuppression; Immunosuppressive Agents; Inbreeding; Infusion procedures; Injury; Intracranial Hypertension; Life; Liver; Liver Failure; Metabolic; Methods; Modeling; Monkeys; Natural regeneration; Organ Transplantation; Patients; Pharmaceutical Preparations; Portal vein structure; Pre-Clinical Model; Reporting; Research; Rest; Source; Testing; Therapeutic immunosuppression; Time; Transplant Recipients; Transplantation; Xenograft procedure; body system; graft failure; graft function; immunosuppressed; improved; improved outcome; innovation; interest; liver allograft; liver function; liver injury; liver transplantation; nonhuman primate; novel strategies; pre-clinical; public health relevance; repaired; research study; theories

 DESCRIPTION (provided by applicant): The proposed research tests whether swine hepatocyte xenografts can improve survival in acute or fulminant liver failure. Acute liver failure poses an extraordinary clinical challenge. This challenge reflects in part the complex, life-threatening pathophysiology of the condition. However, it also reflects the view that approximately one third, and possibly more of those most severely afflicted with acute liver failure, could recover liver function if effective artificial or biological support were available. Instead, these patients typically undergo emergency orthotopic liver transplantation or they die. Anecdotal reports in humans and experiments in animals suggest that transplantation of isolated hepatocytes into the damaged liver, by infusion in the portal vein, might obviate the need for organ transplantation in patients with liver failure. Since human livers are in short supply, interest has focused on use of hepatocytes from animals, especially swine, the hepatocytes of which are sometimes incorporated in artificial liver support devices. Our research employs the first reproducible model of acute liver failure in non-human primates and new approaches to imaging grafted cells and assaying immune responses that ensue. With these innovations, the proposed research will reveal, in a pre-clinical setting, 1) the extent to which swine hepatocyte xenografts can support life and reverse the key pathophysiologic manifestations of acute liver failure, 2) whether immune or non-immune barriers limit the impact of the grafts or cause the grafts to fail, and 3) the conditions in which failure can be reversed b increased immunosuppression and/or provision of another hepatocyte xenograft. Besides potentially providing proof of principle, the research may advance broader application of the model of acute liver failure, approaches to tracing the fate of grafted cells and the immune response they provoke.

 描述（由适用提供）：拟议的研究测试是猪肝细胞Xenographograptic是否可以改善急性或暴发性肝衰竭的生存率。急性肝衰竭 提出了一个非凡的临床挑战。这一挑战部分反映了该病情的复杂，威胁生命的病理生理学。但是，这也反映了这样的观点，即如果有有效的人工或生物学支持，大约三分之一的人可能会恢复最严重遭受急性肝衰竭的人，可能会恢复肝功能。 取而代之的是，这些患者通常接受紧急矫形肝移植或死亡。人类中的轶事报道和动物实验表明，通过输注门静脉，将分离的肝细胞移植到受损的肝脏中，可能会消除肝衰竭患者的器官移植。由于人类的生命缺乏供应，因此有趣的是使用动物（尤其是猪）的肝细胞使用，其肝细胞有时会纳入人造肝脏支撑装置中。我们的研究员工在非人类隐私中的急性肝衰竭的第一个可再现模型，以及想象图形细胞并主张随之而来的免疫调查的新方法。通过这些创新，拟议的研究将在临床前的环境中揭示，1）猪肝肝细胞Xenographographics在多大程度上可以维持生命并逆转急性肝衰竭的关键病理生理表现，2）免疫或非免疫障碍是否会限制移植物的影响或导致移植物的影响和3岁的疾病，并导致或3岁的疾病，并且3）的疾病和3）的疾病或3）提供另一个肝细胞特征。除了提供原理证明外，该研究还可以推动急性肝衰竭模型的广播公司的应用，以追踪移植细胞的命运以及它们引起的免疫激素的命运。