Novel Approaches To Achieve Allograft Tolerance

在非人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阻断的治疗（一种不直接溶淋巴细胞的治疗）是否可以通过使用增强T细胞活化诱导的细胞死亡（AICD）的药物（例如雷帕霉素或甲氨蝶呤（MTX））的伴随治疗而变得更有效。2)确定基于短期共刺激阻断的治疗，一种不直接淋巴溶解的治疗，可以通过使用细胞减少性抗CD 8 mAb的伴随治疗变得更有效。3)确定基于短期共刺激阻断的治疗是否可以通过使用阻断和暂时破坏IL-15/IL-15 R网络的Ig相关融合蛋白（突变体IL-15/Fc）的伴随治疗而变得更有效。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性的细胞和分子事件。5)确定是否可以监测从潜在耐受性治疗中退出的器官移植受者的早期移植物排斥反应，以便在需要时，在不可逆排斥反应发生之前可以开始适当的免疫抑制治疗。6)确定是否可以通过从该项目的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in the acquisition and maintenance of allograft tolerance. 5) determine whether organ transplant recipients, who are withdrawn from a potentially tolerizing therapy can be monitored for incipient graft rejection so that, when needed, appropriate immunosuppressive therapy can be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.