IMMUNOGENICITY OF A XENOGENEIC BIOARTIFICAL LIVER

异种生物人工肝的免疫原性

• 批准号: 2747884
• 负责人: SCOTT L NYBERG
• 金额: $ 10.8万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-15 至 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2747884
• 关键词: animal tissue; antibody titering; biomaterial development /preparation; cell death; cell transplantation; cellular immunity; cytokine; dogs; liver cells; liver function; liver transplantation; membrane permeability; swine; tissue engineering; transplantation immunology; xenotransplantation

Liver failure is a serious problem that effects thousands of people in the United States each year. A new form of therapy, the bioartificial liver (BAL), is in development to provide liver function to patients with liver failure prior to transplantation or until recovery of the native liver. Results of preliminary trials of a BAL containing pig hepatocytes or human C3A cells have been encouraging, but improvement is still necessary. Cell death, for example, occurs during perfusion of the BAL and limits device function and the duration of therapy. The mechanism of hepatocyte death is poorly understood, and may result from immune-mediated injury. According to this hypothesis, immune activation during a first BAL exposure may cause an accelerated response during subsequent BAL exposures. Though the BAL contains a membrane to block contact of the patient's circulation and non-autologous hepatocytes in the device, pores in the membrane allow the release of antigenic material from the BAL and the entrance of molecular mediators of rejection from the patient. The following three hypotheses will be tested as specific aims of this study: (1) the death of hepatocytes in the BAL occurs by an immune-mediated mechanism; (2) The immune response of recipients to BAL therapy is increased during secondary exposures; (3) The immune response of the recipient adversely effects the functionality of the BAL. The immune response to the BAL will be characterized by changes in antibody titers, cellular activation, and cytokine expression in the recipient. The mechanism of cell death in the BAL will be determined by histological and biochemical examination of hepatocytes after BAL therapy. Hepatocyte viability and deposition of recipient proteins in the BAL will be measured and used to assess the effects of immune response in the BAL. The BAL will be tested in healthy dogs to provide a normal, primary immune response and to allow a second BAL treatment three weeks after the first treatment. Hollow fiber membranes with mean pore diameter of 200 nanometer and 5 nanometer (approximately 100 kD molecular weight cut-off) will be compared, since these pore sizes are relevant to current clinical trials of the BAL. A better understanding of the immune response in recipients will improve BAL therapy.

肝衰竭是一个严重的问题，每年影响美国成千上万的人。 一种新的形式的治疗形式，即生物人工肝（BAL），正在开发为肝功能提供肝功能，以在移植前或直到恢复天然肝脏。 含有猪肝细胞或人类C3A细胞的BAL初步试验的结果令人鼓舞，但仍然需要改善。 例如，细胞死亡发生在BAL灌注和限制器械功能和治疗持续时间期间。 肝细胞死亡的机制知之甚少，可能是由于免疫介导的损伤而造成的。 根据这一假设，在首次BAL暴露期间的免疫激活可能会在随后的BAL暴露期间引起加速反应。 尽管BAL含有膜，以阻止设备中患者的循环和非自动肝细胞的接触，但膜中的孔允许从BAL释放抗原材料，并从患者那里释放出排斥反应的分子介体。 以下三个假设将作为本研究的特定目的进行检验：（1）BAL中肝细胞的死亡是由免疫介导的机制发生的； （2）接受者对BAL治疗的免疫反应在继发性暴露期间增加； （3）受体的免疫反应对BAL的功能产生不利影响。 对BAL的免疫反应将以抗体滴度，细胞激活和受体中细胞因子表达的变化为特征。 BAL中细胞死亡的机制将由BAL治疗后的组织学和生化检查确定。 将测量并用于评估BAL中免疫反应的作用，并用于评估BAL中受体蛋白的肝细胞生存力和沉积。 BAL将在健康的狗中进行测试，以提供正常的原发性免疫反应，并在第一次治疗后三周允许第二次BAL治疗。 将比较具有平均孔直径为200纳米和5纳米（约100 kD分子量截止）的空心纤维膜，因为这些孔径与当前BAL的临床试验有关。 更好地了解接受者中免疫反应将改善BAL疗法。