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

将免疫抑制剂靶向递送至移植物内皮以预防肺移植中的排斥反应

• 批准号: 10693272
• 负责人: Carl Atkinson
• 金额: $ 40.54万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10693272
• 关键词: Binding; Biological; Brain Death; Cell Adhesion; Cell Adhesion Molecules; Cells; Data; Development; Endothelium; Goals; Graft Rejection; Graft Tolerance; Harvest; Immune; Immune response; Immunosuppression; Immunosuppressive Agents; Inflammatory; Intercellular adhesion molecule 1; Knowledge; Lung; Lung Transplantation; Lung diseases; Lymphocyte; Organ; Outcome; Patients; Peptides; Prevention; Prevention approach; Procedures; Reperfusion Injury; Solid; Survival Rate; T-Lymphocyte; Transplantation; Up-Regulation; Validation; Vascular Cell Adhesion Molecule-1; cell type; cytokine; design; experience; immune cell infiltrate; improved; lung failure; lymphoid organ; nano; new therapeutic target; novel; novel strategies; prevent; targeted delivery; trafficking

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.

项目摘要 肺移植（LTX）仍然是终末期肺部疾病患者的唯一可用治疗方法。 然而，与其他固体器官（SOT）的移植相比，LTX后的结果更糟。免疫抑制 LTX中使用的制度是从其他SOT的经验中得出的。但是，这种策略可能存在缺陷， 由于最近的数据表明，肺部免疫反应明显差异。与其他SOT不同 在肺部淋巴细胞中，排斥反应的开始取决于细胞运输到嫁接淋巴管的器官 启动发生在肺移植本身中。因此，迫切需要开发新颖的方法来改进 LTX生存。由于大多数移植到接受者的肺都是从大脑死亡（BD）供体中收获的，因此有 必须考虑必须考虑的重要生物学后果，尤其是大规模的炎症活性和 细胞因子释放，从而导致细胞类型的全腹激活。这包括上调 细胞粘附分子（CAM），特别是VCAM-1和ICAM-1，启动移植物进行排斥。缺血 - 由移植程序引起的再灌注损伤有可能使该凸轮激活更高。我们 因此，建议研究一种新型的双功能方法来预防LTX排斥反应，以此为重点 纳米剂的开发有可能阻止基于CAM的移植物伴随着与 提供免疫抑制剂。具体而言，我们将：1）确定能够结合ICAM-1或VCAM-的肽 - 1具有抑制免疫细胞运输和T细胞启动的能力； 2）研究高级双功能 纳米剂旨在定位在肺部并抑制排斥反应。总体目标是对小说的验证 有针对性的治疗方案，有可能消除对全身免疫抑制的需求。