Monocytic-MDSCs as resolution mediators of post-transplant lung ischemia-reperfusion injury

单核细胞-MDSC作为移植后肺缺血再灌注损伤的解决介质

• 批准号: 10677290
• 负责人: Victoria Leroy
• 金额: $ 4.77万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10677290
• 关键词: Adoptive Transfer; Attenuated; Bone Marrow; Cell Therapy; Cells; Coculture Techniques; Complex; Cytotoxic T-Lymphocytes; Data; Development; Emergency Situation; Functional disorder; Goals; Graft Tolerance; Heart; Hematopoietic stem cells; Hilar; Histology; Human; Immature Granulocyte; Immature Monocyte; Immune; Immune response; Immunohistochemistry; Immunology; In Vitro; Inbred BALB C Mice; Inflammation; Inflammatory; Inflammatory Response; Injury; Kidney; Laboratories; Ligation; Lung; Lung Transplantation; Malignant Neoplasms; Measures; Mediating; Mediator; Methods; Modeling; Molecular; Mus; Myelogenous; Myeloid Cells; Myeloid Progenitor Cells; Myeloid-derived suppressor cells; Myelopoiesis; National Research Service Awards; Neutrophil Activation; Null Lymphocytes; Operative Surgical Procedures; Organ; Organ Transplantation; Outcome; Pathologic; Pathway interactions; Patients; Phase; Phenotype; Population; Population Heterogeneity; Predisposition; Process; Production; Proliferating; Property; Pulmonary Inflammation; Reperfusion Injury; Reporting; Research; Resolution; Role; Signal Pathway; Skin; Solid; Sterility; Survival Rate; Techniques; Testing; Therapeutic; Time; Training; Transplantation; Transplantation Immunology; cell type; clinically relevant; cytokine; experimental study; granulocyte; immune activation; immunoregulation; implantation; improved; in vitro Model; insight; interest; lung injury; lung ischemia; monocyte; mortality; mouse model; neutrophil; post-transplant; prevent; pulmonary function; statistics; success; therapeutic target; transplant model

PROJECT SUMMARY Post-lung transplant ischemia reperfusion injury is an unavoidable insult that occurs early in the post-transplant period and can cause significant dysfunction in an otherwise healthy graft. This injury is characterized by a robust inflammatory response that when unresolved, can lead to both short- and long-term mortality, ultimately hindering success rates of lung transplantation. The mechanisms that facilitate the resolution of inflammation, and specifically the resolution of this sterile insult, are not well characterized, and thus represent an attractive research opportunity that could uncover therapeutic targets. Recently, transplant research has focused on the therapeutic potential of innate cells that suppress immune response, referred to as Myeloid-Derived Suppressor Cells (MDSCs). This is a heterogeneous population of cells made up of granulocytic-like (G-MDSC) and monocytic-like (M-MDSCs) immature myeloid cells with potent immunosuppressive properties. Their role as master immunosuppressive regulators has been extensively elucidated in cancer settings, with findings translatable, but not confirmed, in transplantation. The proposed F31 NRSA application will use an experimental lung IRI model, a murine orthotopic lung transplant model, and in vitro methods to test the overall hypothesis that the M-MDSC subset facilitates the resolution of post-lung transplant ischemia reperfusion injury. In Aim 1, I will test the hypothesis that M-MDSC facilitate the resolution of lung IRI in an experimental hilar-ligation induced lung injury model through modulation of specific immune cell activation. In Aim 2, I will test the hypothesis that M-MDSCs act in an immunosuppressive manner to reduce lung injury in a murine orthotopic lung transplant model. This project will reveal insights into the actions of M-MDSCs in the lung which is crucial to understanding their full potential as a cellular therapy in the induction of graft tolerance.

项目摘要 肺移植后缺血再灌注损伤是一种不可避免的损伤，发生在移植后早期， 并且可能导致健康移植物的显著功能障碍。这种损伤的特点是 炎症反应，如果不解决，可导致短期和长期死亡，最终 阻碍了肺移植的成功率。促进炎症消退的机制， 特别是这种无菌损伤的解决，没有很好地表征，因此代表了一种有吸引力的 研究机会，可以发现治疗目标。最近，移植研究的重点是 抑制免疫应答的先天细胞（称为髓源性抑制因子）的治疗潜力 细胞（MDSC）。这是由粒细胞样（G-MDSC）和 单核细胞样（M-MDSC）未成熟的骨髓细胞，具有有效的免疫抑制特性。家作用 在癌症环境中，免疫抑制调节剂已被广泛阐明， 在移植中是可翻译的，但尚未得到证实。拟议的F31 NRSA应用程序将使用实验性的 肺IRI模型、鼠原位肺移植模型和检验总体假设的体外方法 M-MDSC亚群促进肺移植后缺血再灌注损伤的解决。在目标1中， 将检验M-MDSC促进实验性肺门结扎诱导的肺IRI消退的假设。 通过调节特异性免疫细胞活化的肺损伤模型。在目标2中，我将检验以下假设： M-MDSC以免疫抑制方式减少小鼠原位肺移植中的肺损伤 模型该项目将揭示M-MDSC在肺中的作用，这对于理解 它们作为诱导移植耐受的细胞疗法的全部潜力。