Novel Approaches To Achieve Allograft Tolerance

非人灵长类动物肾移植模型的SPECIFIC AIMS是：1)确定短期共刺激阻断疗法（一种不直接淋巴溶解的治疗方法）是否可以通过与增强t细胞活化诱导细胞死亡（AICD）的药物（如雷帕霉素或甲氨蝶呤（MTX））联合治疗而更有效。2)确定短期共刺激阻断疗法，一种不直接淋巴溶解的治疗方法，可以通过使用细胞减少抗cd8单抗的同时治疗而更有效。3)通过使用阻断并暂时破坏IL-15/IL-15R网络的igg相关融合蛋白（突变的IL-15/Fc）联合治疗，确定短期共刺激阻断疗法是否更有效。4)确定供体反应性t细胞频率的时间相关模式，以及参与获得和维持同种异体移植物耐受的细胞和分子事件。5)确定退出潜在耐受治疗的器官移植受者是否可以监测早期移植排斥反应，以便在需要时，在不可逆排斥反应发生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每个组成部分的共同努力中获得的知识来建立理想的治疗和诊断方案。

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in the acquisition and maintenance of allograft tolerance. 5) determine whether organ transplant recipients, who are withdrawn from a potentially tolerizing therapy can be monitored for incipient graft rejection so that, when needed, appropriate immunosuppressive therapy can be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.