Graft-Resident CD11c Cells are Critical for the Maintenance of Tolerance Following Lung Transplantation

移植物驻留 CD11c 细胞对于肺移植后维持耐受性至关重要

• 批准号: 10066573
• 负责人: Margaret Shea Harrison
• 金额: $ 6.74万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10066573
• 关键词: Antibodies; B-Cell Activation; B-Lymphocytes; Blinded; Bronchus-Associated Lymphoid Tissue; CCL17 gene; CCL22 gene; CD11 Antigens; CD8-Positive T-Lymphocytes; Cell Communication; Cells; Data; FOXP3 gene; Flow Cytometry; Graft Rejection; Helper-Inducer T-Lymphocyte; Histology; ITGAX gene; Immune; Immune response; Immunohistochemistry; Immunosuppression; Infiltration; Interferon Type II; Laboratories; Lung; Lung Transplantation; Lymphoid; Lymphoid Tissue; Maintenance; Mediating; Methods; Movement; Mus; Organ; Organ Transplantation; Outcome; Pathway interactions; Pattern; Play; Production; Refractory; Regimen; Regulatory T-Lymphocyte; Reporting; Research; Role; Secondary to; Solid; T-Cell Receptor; T-Lymphocyte; Testing; Time; Tissue Grafts; Tissues; Transplant Recipients; Transplantation; base; experience; experimental study; improved outcome; lung allograft; macrophage-derived chemokine; mouse model; novel; novel imaging technology; novel therapeutics; receptor; recruit; response; secondary lymphoid organ; spatial relationship; trafficking; transplant model; two photon microscopy

PROJECT SUMMARY/ABSTRACT: Long-term survival after lung transplantation remains profoundly limited by graft rejection. Immunosuppression for lung recipients is based on experiences with solid organ transplants, but may be having deleterious effects to the survival of pulmonary grafts as the fate of the transplanted lungs is determined by local immune cell interactions within the graft itself. Bronchus-associated lymphoid tissue (BALT) forms in tolerant lung allografts and is important for the maintenance of tolerance. BALT is rich in Foxp3+ regulatory T cells that aggregate around CD11c+ cells. Depleting graft-resident Foxp3+ T cells or CD11c+ cells results in antibody mediated rejection. Exactly how cells interact within the BALT to regulate tolerance remains unknown. Our laboratory surprisingly found that the abundance of Foxp3+ T cells were not impacted by depletion of CD11c+ cells. CCL17 and CCL22 are chemokines expressed by CD11c+ cells that can engage CCR4, a receptor predominantly expressed on regulatory T cells. Preliminary data from our laboratory show that CCL17 and CCL22 are expressed at significantly higher levels by CD11c+ cells in tolerant lung grafts when compared to CD11c+ cells in rejecting lungs. We aim to determine whether CD11c+ cells maintain tolerance after lung transplantation by mediating the spatial organization of Foxp3+ cells within the graft. A previously established model of mouse lung re- transplantation will be used to test our hypotheses. Results will be analyzed using a combination of methods, including flow cytometry, immunohistochemistry and blinded histology analysis. A novel imaging technology, known as intravital two-photon microscopy, will be used in multiple experiments to study the movement and spatial relationships of Foxp3+ cells and CD11c+ cells in real time. The results of our proposal will provide a framework to develop novel therapies to improve outcomes for lung transplant patients.

项目概要/摘要： 肺移植后的长期生存仍然受到移植排斥的严重限制。 肺受者的免疫抑制是基于实体器官移植的经验，但可能 对肺移植物的存活产生有害影响，因为移植肺的命运 由移植物本身内的局部免疫细胞相互作用决定。支气管相关淋巴 组织（BALT）在耐受性肺同种异体移植物中形成，对于维持耐受性很重要。巴尔特 富含 Foxp3+ 调节性 T 细胞，聚集在 CD11c+ 细胞周围。耗尽移植物驻留的 Foxp3+ T 细胞或 CD11c+ 细胞会导致抗体介导的排斥反应。细胞在 BALT 内到底如何相互作用 调节耐受性仍然未知。我们的实验室令人惊讶地发现 Foxp3+ 的丰度 T 细胞不受 CD11c+ 细胞耗竭的影响。 CCL17 和 CCL22 是表达的趋化因子 CD11c+ 细胞可以与 CCR4 结合，CCR4 是一种主要在调节性 T 细胞上表达的受体。 我们实验室的初步数据显示，CCL17 和 CCL22 的表达量明显更高 与排斥肺中的 CD11c+ 细胞相比，耐受性肺移植物中 CD11c+ 细胞的水平。我们 旨在确定 CD11c+ 细胞是否通过介导肺移植后维持耐受性 移植物内 Foxp3+ 细胞的空间组织。先前建立的小鼠肺模型 移植将用于检验我们的假设。将使用以下组合来分析结果 方法，包括流式细胞术、免疫组织化学和盲法组织学分析。一本小说 成像技术，称为活体双光子显微镜，将用于多个实验 实时研究 Foxp3+ 细胞和 CD11c+ 细胞的运动和空间关系。结果 我们的提案将提供一个框架来开发新疗法，以改善肺部疾病的结果 移植患者。