Novel Approaches To Achieve Allograft Tolerance

实现同种异体移植耐受的新方法

• 批准号: 6532898
• 负责人: TERRY B. STROM
• 金额: $ 55.61万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6532898
• 关键词: Macaca fascicularis; artificial immunosuppression; biological models; homologous transplantation; immune tolerance /unresponsiveness; interleukin 15; kidney transplantation; monoclonal antibody; nonhuman therapy evaluation; transplant rejection; transplantation immunology

The SPECIFIC AIMS in non-human primate kidney transplant model are to: 1) determine whether short-term costimulation blockade based therapy, a treatment that is not directly lympholytic, can be made more effective through use of concomitant treatment with drugs that enhance T-cell activation induced cell death (AICD), e.g. rapamycin or methotrexate (MTX). 2) determine short-term costimulation blockade based therapy, a treatment that is not directly lympholytic, can be made more effective through use of concomitant treatment with a cytoreductive anti-CD8 mAb. 3) determine whether short-term costimulation blockade based therapy can be made more effective through use of concomitant treatment with an Ig-related fusion protein (mutant IL-15/Fc) that blocks and temporarily destroys the IL-15/IL-15R network. 4) identify the time-related pattern of donor reactive T-cell frequency as well as cellular and molecular events that are involved in the acquisition and maintenance of allograft tolerance. 5) determine whether organ transplant recipients, who are withdrawn from a potentially tolerizing therapy can be monitored for incipient graft rejection so that, when needed, appropriate immunosuppressive therapy can be instituted before irreversible rejection takes place. 6) determine whether an idealized therapeutic and diagnostic protocol can be established through knowledge gained from the combined efforts of each of the components of this project.

非人类灵长类动物肾移植模型中的具体目的是：1）确定基于短期共刺激性封锁的治疗（一种不是直接淋巴结液）是否可以通过使用与T细胞激活诱导的细胞死亡（AICD）的药物一起使用的药物来更有效，例如。雷帕霉素或甲氨蝶呤（MTX）。 2）确定无法直接淋巴结液的疗法基于短期共刺激的治疗，可以通过使用伴有细胞还原性抗CD8 MAB的伴随治疗来使其更有效。 3）确定是否可以通过使用与Ig相关的融合蛋白（突变的IL-15/FC）使用伴随治疗，从而使基于短期共刺激的治疗能够更有效，该蛋白（突变的IL-15/FC）会暂时破坏IL-15/IL-15R网络。 4）确定供体反应性T细胞频率的时间相关模式以及参与同种异体移植耐受性的获取和维持所涉及的细胞和分子事件。 5）确定是否可以监测从潜在耐受治疗的人的器官移植受者进行初期的移植物排斥反应，以便在需要时可以在不可逆拒绝之前进行适当的免疫抑制治疗。 6）确定是否可以通过从本项目的每个组成部分的综合努力中获得的知识来确定理想化的治疗和诊断方案。