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实验性手术转变为注定死亡的患者的成功解决方案。然而，这些药物的使用由于其毒性而导致显著的发病率和死亡率。最近的数据表明，在移植物部位的局部免疫抑制将增加移植物的存活率，并减少免疫抑制剂在其他器官中的毒性。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。我们建议使用免疫抑制剂的大分子前药，其优先在肝脏中积累，用于肝移植中局部免疫抑制的目的。具体而言，我们将研究甲基强的松龙（MP）的葡聚糖前药在大鼠中的组织蓄积和免疫抑制作用。我们的假设是MP的葡聚糖前药将优先在肝脏中积累，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。前药将通过经由各种接头将葡聚糖连接到MP来合成，并且将选择最佳接头。然后在大鼠中测试所选前药的药代动力学，包括前药给药的剂量和频率。此外，将前药对全身和局部免疫应答的作用与母体药物的作用进行比较。最后，将在原位大鼠肝移植模型中比较前药与母体药物在预防同种异体移植物排斥反应中的有效性。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。这些研究意义重大，因为它们最终将导致与目前用于肝移植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.