NPH RENAL & SKIN TRANSPLANTATION FOR ALLOSPECIFIC TOLERANCE INDUCTION

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 在本研究的第一阶段（2007年11月至2008年2月），我们进行了所有移植（n=7），没有技术性移植物丢失，并且与对照组（n=4）和实验组（n=3）相比， 未处理的历史对照。然而，在对照组和实验组中，我们已经记录了与先前发表的与雷帕霉素相关的副作用一致的副作用（蒙哥马利et.等，Am J Transplant. 2002年）。鉴于两组中临床症状、大体尸检观察结果和与当前观察到的毒性相关的组织学结果的一致性，我们排除了Genz-29155作为致病因子。我们减少了 雷帕霉素给药方案的目标是降低5-10 mg/ml的血液水平。 为了确保适当的剂量调整和动物福利，两只猴子被给予新的“低剂量雷帕霉素方案”45天（不进行移植）。在整个45天给药期间或通过尸检进行的大体和组织学检查（2008年3月至4月）中，未观察到毒性的临床体征或症状。 结果，肾同种异体移植的第二阶段开始，然而，所有剩余的受试者被给予所提出的减少的雷帕霉素剂量，目标血液水平为5-10 ng/ml;对照组（n=2）和实验组（n = 10）。 （n=4）。在第二阶段，两组均未观察到不良副作用。与对照组（雷帕霉素/媒介物）相比，在实验组（Genz-29155/雷帕霉素）中观察到肾同种异体移植物无排斥存活的延长，然而，避免动物毒性所需的减少的雷帕霉素剂量不足以充分评估雷帕霉素与Genz-29155抑制同种异体移植物排斥的协同潜力。总之，PI和Genzyme Corp均认为该非人灵长类动物肾同种异体移植模型不足以继续Genz-29155与雷帕霉素的研究和临床前开发。

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. In the first phase of this study (Nov 2007 - Feb 2008), we performed all transplants (n=7) without technical graft loss and were able to prolong the onset of allograft rejection in both the control (n=4) and experimental (n=3) groups compared to untreated historic controls. However, in both the control and experimental groups, we have documented side effects consistent with previously published side effects associated with rapamycin (Montgomery et. al. Am J Transplant. 2002). Given the consistent nature of the clinical symptoms, gross necropsy observations, and histological findings associated with current observed toxicities present in both groups, we ruled out Genz-29155 as the causative agent. We reduced the rapamycin dosing schedule to target decreased blood levels of 5-10 mg/ml. To ensure proper dosing modification and animal welfare, two monkeys were administered the new 'low dose rapamycin regimen' for 45 days (no transplants were performed). No clinical signs or symptoms of toxicity were observed throughout the 45 day treatment period or on gross and histological examination by necropsy (March-April 2008). As a result, a second phase of renal allograft transplants commenced, however, all remaining subjects were administered the proposed reduced rapamycin dosing, targeting blood levels of 5-10 ng/ml; control group (n=2) and experimental group (n=4). No adverse side effects were observed in either group in this second phase. Prolongation of renal allograft rejection free survival was observed in the experimental group (Genz-29155/rapamycin) compared to the control group (rapamycin/vehicle), however the reduced rapamycin dosing, required to avoid animal toxicities, was insufficient to adequately assess the synergistic potential of rapamycin with Genz-29155 to inhibit allograft rejection. In conclusion, both the PI and Genzyme Corp decided that this non-human primate renal allograft model was not sufficient to continue the investigation and pre-clinical development of Genz-29155 with rapamycin.