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个实验程序转变为一个成功的解决方案，否则将注定死亡的患者。然而，由于这些药物的毒性，它们的使用导致了显著的发病率和死亡率。最近的数据表明，在移植物移植部位进行局部免疫抑制可以提高移植物的存活率，并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存在一些局限性，严重阻碍了其临床应用。我们建议在肝移植中使用免疫抑制剂的大分子前药，这些药物在肝脏中优先积累，以达到局部免疫抑制的目的。具体来说，我们将研究甲基强的松龙（MP）右旋糖酐前药在大鼠体内的组织积累和免疫抑制特征。我们的假设是，MP的葡聚糖前药会优先在肝脏中积累，在肝脏中逐渐再生活性药物，导致肝移植中持续的局部免疫抑制。将右旋糖酐通过不同的连接体附着在MP上合成前药，并选择最佳的连接体。所选前药的药代动力学将在大鼠中测试前药给药的剂量和频率。此外，前药对全身和局部免疫反应的影响将与母体药物进行比较。最后，在原位大鼠肝移植模型中，比较前药与母药预防同种异体移植排斥反应的效果。我们期望这种方法将大大减少对大鼠移植肝进行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当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.