Targeted delivery of immunosuppressive agents to the graft endothelium for the prevention of rejection in lung transplantation

项目摘要 肺移植(LTX)仍然是终末期肺部疾病患者唯一可用的治疗方法。 然而，与其他实体器官移植(SOT)相比，LTX的结果更差。免疫抑制 LTX中使用的制度是从其他SOT的经验中得出的。然而，这种战略可能是有缺陷的， 因为最近的数据表明，肺部的免疫反应存在明显的差异。与其他SOT不同 在肺淋巴细胞中，排斥反应的启动依赖于细胞向移植物引流淋巴器官的运输 启动过程发生在肺移植物本身。因此，迫切需要开发新的方法来改进 LTX存活。由于大多数移植给受者的肺是从脑死亡(BD)捐赠者那里获得的，因此有 必须考虑的重要生物后果，特别是大规模炎症活动和 细胞因子的释放，导致多种细胞类型的激活。这包括上调 细胞黏附分子(CAM)，特别是VCAM-1和ICAM-1，为移植物的排斥反应做好准备。缺血症- 移植过程引起的再灌注损伤有可能使这种CAM激活更高。我们 因此，建议研究一种新的双功能方法来预防LTX排斥反应，重点是 纳米制剂的发展具有潜在的阻断基于CAM的预充剂的移植物伴随着 运送免疫抑制药。具体地说，我们将：1)鉴定能够结合ICAM-1或VCAM-1的多肽- 1)具有抑制免疫细胞转运和T细胞启动的能力；2)研究先进的双功能 设计用于定位到肺部并抑制排斥反应的纳米制剂。总体目标是对一部小说进行验证 有针对性的治疗方案，有可能消除全身免疫抑制的需要。

Project Abstract Lung transplantation (LTx) remains the only available treatment for patients with end-stage pulmonary disease. Yet, outcomes after LTx are worse compared to the transplant of other solid organs (SOT). Immunosuppressive regimes used in LTx have been derived from experiences with other SOTs. Yet, such a strategy may be flawed, as recent data has demonstrated clear differences in the immune responses in the lung. Unlike other SOTs where initiation of rejection depends on cell trafficking to graft-draining lymphoid organs, in the lung lymphocyte priming occurs in the lung graft itself. There is thus an urgent need to develop novel approaches to improve LTx survival. As most lungs transplanted into recipients are harvested from brain dead (BD) donors, there are important biological consequences that must be considered, particularly the massive inflammatory activity and cytokine release, which results in the activation of a panoply of cell types. This includes the upregulation of cellular adhesion molecules (CAM), in particular VCAM-1 and ICAM-1, priming the graft for rejection. Ischemia- reperfusion injury caused by the transplant procedure has the potential to drive this CAM activation higher. We thus propose to investigate a novel bi-functional approach to the prevention of LTX rejection, focused on the development of nanoagents with the potential to block CAM-based priming of the graft concomitant with the delivery of immunosuppressives. Specifically, we will: 1) Identify peptides capable of binding ICAM-1 or VCAM- 1 with the ability to suppress immune cell trafficking and T cell priming; and 2) Investigate advanced bi-functional nanoagents designed to localize to the lung and inhibit rejection. The overall goal is the validation of a novel targeted therapeutic regime with the potential to obviate the need for systemic immunosuppression.