CALCINEURIN INHIBITOR SPARING PROTOCOL IN PEDIATRIC KIDNEY TRANSPLANTATION (CN-

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。移植后护理和免疫抑制的改善导致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，其中一些药物可能加速慢性同种异体移植肾病。研究人员提出，使用tor抑制剂西罗莫司，将在活体供体移植后免疫抑制中消除钙调磷酸酶抑制剂的需要。如果这项试点研究成功，研究人员将扩大方案，包括尸体供体受体和西罗莫司覆盖下的移植前供体特异性输血（DST）。这种移植前故意暴露于供体抗原可能导致供体免疫进一步抑制。这一长期建议是基于临床前观察，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细胞的活化诱导细胞死亡（AICD）。这些方案将包括加强免疫监测，旨在尽早发现抗供体反应性。患者将接受人源抗cd25单克隆抗体DACLUZIMAB，分5次给药，为期2个月。第一剂将在术中给药，随后的剂量将每两周给药一次，直到移植后8周。维持性免疫抑制也将从第1天开始给予。

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.