Local Immunosuppression for Liver Transplantation

描述(由申请人提供)：新的免疫抑制药物的引入已经将肝移植从一种实验程序转变为一种成功的解决方案，用于原本注定要死亡的患者。然而，由于它们的毒性，这些药物的使用已经导致了显著的发病率和死亡率。最近的研究表明，移植物部位的局部免疫抑制可以提高移植物的存活率，降低免疫抑制剂对其他器官的毒性。然而，目前的局部免疫抑制方法有一些局限性，这严重阻碍了它们的临床应用。我们建议在肝移植中使用免疫抑制剂的大分子前体药物，这些药物优先聚集在肝脏，以达到局部免疫抑制的目的。具体地说，我们将研究甲基强的松龙(MP)的葡聚糖前药在大鼠体内的组织蓄积和免疫抑制情况。我们的假设是，MP的葡聚糖前体药物将优先在肝脏中积聚，在那里它逐渐再生活性药物，导致肝移植中持续的局部免疫抑制。通过不同的连接物将葡聚糖连接到MP上，合成前药，并选择最佳连接物。然后，将根据前药给药的剂量和频率在大鼠身上测试所选前药的药代动力学。此外，前药对全身和局部免疫反应的影响将与母药进行比较。最后，在大鼠原位肝移植模型中，将前药与母药在预防同种异体移植排斥反应中的有效性进行比较。我们期望这种方法将大大减少大鼠移植肝脏有效免疫抑制所需的药物剂量。这些研究具有重要意义，因为它们最终将导致与目前肝移植中使用的免疫抑制方案相关的发病率和死亡率的大幅降低。

DESCRIPTION (provided by applicant): Introduction of new immunosuppressive drugs has transformed liver transplantation from an experimental procedure to a successful solution for patients who are otherwise doomed to death. However, the use of these drugs has resulted in significant morbidity and mortality due to their toxicity. Recent data indicates that local immunosuppression at the site of transplanted graft will increase graft survival and reduce the toxicity of immunosuppressive agents in other organs. However, current methods of local immunosuppression have several limitations, which seriously hamper their clinical use. We propose here to use macromolecular prodrugs of immunosuppressants, which preferentially accumulate in the liver, for the purpose of local immunosuppression in liver transplantation. Specifically, we will investigate the tissue accumulation and immunosuppressive profile of a dextran prodrug of methylprednisolone (MP) in rats. Our hypothesis is that the dextran prodrug of MP will preferentially accumulate in the liver, where it gradually regenerates the active drug, resulting in sustained local immunosuppression in liver transplantation. Prodrugs will be synthesized by attaching dextran to MP via various linkers, and an optimum linker will be selected. The pharmacokinetics of the selected prodrug will then be tested in rats with respect to the dose and frequency of prodrug administration. Further, the effects of the prodrug on the systemic and local immune response will be compared with those of the parent drug. Finally, the effectiveness of the prodrug in prevention of allograft rejection will be compared with those of the parent drug in an orthotopic rat liver transplantation model. It is our expectation that this approach will substantially reduce the drug dose needed for effective immunosuppression of transplanted livers in rats. These studies are significant because they will eventually lead to a substantial reduction in morbidity and mortality associated with the current immunosuppressive protocols used in liver transplantation.