CALCINEURIN INHIBITOR SPARING PROTOCOL IN PEDIATRIC KIDNEY TRANSPLANTATION (CN-

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。移植后护理和免疫抑制的改善导致了儿童肾移植受者越来越成功的短期结果。不幸的是，与免疫抑制剂相关的发病率很高，其中一些药物可能会加速慢性移植物肾病。研究人员提出，TOR抑制剂西罗莫司的使用将使活体供者移植受者在移植后免疫抑制中不再需要钙调神经磷酸酶抑制剂。如果这项试点研究成功，研究人员将把协议扩展到包括身体捐赠者，并包括西罗莫司覆盖范围内的移植前供者特异性输血(DST)。这种在移植前故意暴露于供体抗原的行为可能会进一步导致供体免疫抑制。这一长期建议是基于临床前的观察，即DST加T细胞共刺激阻断(雷帕霉素)可能导致对移植物有害的同种异体反应性T细胞的激活诱导细胞死亡(AICD)。这些方案将包括密集的免疫学监测，旨在尽早发现抗捐赠者的反应性。患者将接受人源化的抗CD25单抗DACLUZIMAB，在2个月内分5次注射。第一剂将在术中给药，后续剂量将在移植后每两周至8周给药一次。维持性免疫抑制也将从第一天开始实施。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Improvements in post transplant care and immunosuppression have led to increasingly successful short-term outcome in pediatric recipients of kidney transplants. Unfortunately, morbidity associated with immunosuppressive agents is substantial and some of these drugs may accelerate chronic allograft nephropathy. The investigators propose that the use of the TOR-inhibitor, sirolimus, will obviate the need for calcineurin inhibitors in post-transplant immunosuppression in recipients of living donor grafts. If this pilot study is successful, the investigators will extend the protocol to include cadaver donor recipients and to a protocol including pre-transplant donor specific transfusions (DST) under sirolimus coverage. This deliberate pre-transplant exposure to donor antigen may lead to donor-immunosuppression even further. This long-term proposal is based on preclinical observations that DST plus T-cell costimulatory blockage (rapamycin) may result in activation induced cell death (AICD) of alloreactive T cells that are harmful to the graft. These protocols will include intense immunologic monitoring which is designed to uncover anti-donor responsiveness as early as possible. Patients will receive humanized anti-CD25 monoclonal antibody DACLUZIMAB, administered in 5 doses over a 2 month period. The first dose will be administered intra-operatively and the subsequent doses will be administered every two weeks up to 8 weeks post transplantation. Maintenance immunosuppression will also be administered beginning on Day -1.