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 在LTx中使用的机制是从其他SOT的经验中得出的。然而，这样的战略可能是有缺陷的， 因为最近的数据已经证明了肺中免疫应答的明显差异。与其他SOT不同 排斥反应的发生依赖于细胞运输到移植物引流淋巴器官，在肺淋巴细胞中 预充发生在肺移植物本身中。因此，迫切需要开发新的方法来改善 LTx存活率。由于大多数移植到受体中的肺是从脑死亡（BD）供体中获得的， 必须考虑的重要生物学后果，特别是大量的炎症活动， 细胞因子释放，其导致一系列细胞类型的激活。这包括上调 细胞粘附分子（CAM），特别是VCAM-1和ICAM-1，引发移植物排斥。局部缺血- 由移植程序引起的再灌注损伤具有驱使这种CAM活化更高的潜力。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 开发具有阻断移植物基于CAM的引发的潜力的纳米剂， 免疫抑制剂的递送。具体而言，我们将：1）鉴定能够结合ICAM-1或VCAM-1的肽， 1）具有抑制免疫细胞运输和T细胞致敏的能力;和2）研究高级双功能免疫应答， 纳米制剂被设计用于定位于肺并抑制排斥反应。总的目标是验证一部小说 靶向治疗方案，有可能消除对全身免疫抑制的需求。

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.