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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要肺移植后缺血再灌注损伤是移植后早期发生的不可避免的损伤期，并可能导致其他健康的移植物出现严重功能障碍。这种损伤的特点是强度大炎症反应如果得不到解决，最终可能导致短期和长期死亡影响肺移植的成功率。促进炎症消退的机制，特别是这种毫无结果的侮辱的解决方案，没有得到很好的表征，因此代表了一种有吸引力的可以发现治疗靶点的研究机会。最近，移植研究的重点是抑制免疫反应的先天细胞的治疗潜力，称为骨髓源性抑制因子细胞（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。他们的角色是主要免疫抑制调节因子已在癌症环境中得到广泛阐明，研究结果在移植中可翻译，但尚未得到证实。拟议的 F31 NRSA 应用将使用实验性肺 IRI 模型、小鼠原位肺移植模型以及检验总体假设的体外方法 M-MDSC 子集有助于解决肺移植后缺血再灌注损伤。在目标 1 中，我将检验 M-MDSC 在实验性肺门结扎诱导的实验中促进肺 IRI 解决的假设通过调节特异性免疫细胞激活来建立肺损伤模型。在目标 2 中，我将检验以下假设： M-MDSC 以免疫抑制方式发挥作用，减少小鼠原位肺移植中的肺损伤模型。该项目将揭示 M-MDSC 在肺部的作用，这对于理解 M-MDSC 的作用至关重要它们作为细胞疗法在诱导移植物耐受方面的全部潜力。