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: 10481101
• 负责人: Carl Atkinson
• 金额: $ 41.85万
• 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/10481101
• 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; Infiltration; Inflammatory; Intercellular adhesion molecule 1; Knowledge; Lung; Lung Transplantation; Lung diseases; Lymphocyte; Organ; Outcome; Patients; Peptides; Prevention; Prevention approach; Procedures; Reperfusion Injury; Respiratory Failure; Solid; Survival Rate; T-Lymphocyte; Transplantation; Up-Regulation; Validation; Vascular Cell Adhesion Molecule-1; base; cell type; cytokine; design; experience; improved; lymphoid organ; 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 后的结果更差。免疫抑制 LTx 中使用的制度源自其他 SOT 的经验。然而，这样的策略可能存在缺陷， 因为最近的数据表明肺部免疫反应存在明显差异。与其他 SOT 不同 排斥反应的开始取决于肺淋巴细胞中的细胞运输至移植物引流淋巴器官 启动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 生存。由于大多数移植到受者体内的肺是从脑死亡 (BD) 供体中获取的，因此 必须考虑的重要生物学后果，特别是大量的炎症活动和 细胞因子的释放，导致多种细胞类型的激活。这包括上调 细胞粘附分子 (CAM)，特别是 VCAM-1 和 ICAM-1，启动移植物的排斥反应。缺血- 移植过程引起的再灌注损伤有可能使 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，重点关注 开发具有阻断基于 CAM 的移植物引发潜力的纳米剂 免疫抑制剂的递送。具体来说，我们将： 1) 鉴定能够结合 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) 研究先进的双功能 设计用于定位于肺部并抑制排斥反应的纳米制剂。总体目标是验证小说 靶向治疗方案有可能消除全身免疫抑制的需要。