Inflammatory Cellular Mechanisms for Establishing and Maintaining Lung Allograft Tolerance

建立和维持肺同种异体移植耐受的炎症细胞机制

基本信息

批准号：
10024445
负责人：
ALEXANDER S. KRUPNICK
金额：
$ 49.81万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-12 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10024445
关键词：
Acute Allograft Tolerance Animals Antibodies Antigen-Presenting Cells Antigens Autologous Bispecific Antibodies CD8-Positive T-Lymphocytes Cells Chronic Clinical Complement Data Dendritic Cells Development Down-Regulation FOXP3 gene Family Feedback Foundations Funding GTP-Binding Protein alpha Subunits, Gs Graft Rejection Graft Survival Graft Tolerance Grant Health Hematopoietic Human Immune response Immunosuppression Inflammation Mediators Inflammatory Interferon Type II Interferons Interleukin-1 Interleukin-1 beta Lung Lung Transplantation Lymphoid Maintenance Mediating Methods NOS2A gene Nitric Oxide Nitric Oxide Synthase Organ Organ Transplantation PD-1/PD-L1 Pathway interactions Play Population Post-Translational Protein Processing Production Protocols documentation Regulatory T-Lymphocyte Role Shapes Signal Transduction Solid Specificity Surface T cell differentiation T-Cell Receptor T-Lymphocyte TNF gene Testing Transplantation Tolerance Work allograft rejection base chemokine cytokine eosinophil experience immunoregulation improved in vivo interstitial lung allograft lung development macrophage member migration monocyte mouse model novel prevent programmed cell death ligand 1 receptor response synaptogenesis

项目摘要

PROJECT SUMMARY/ABSTRACT Studies utilizing the murine model of lung transplantation have helped advance our understanding of lung allograft-specific immunoregulation. Unlike other solid organs, the lung relies on pro- inflammatory feedback loops for establishing and maintaining graft acceptance. We have described that CD8+ T cells, long considered deleterious to solid organ allograft survival, play a critical role in lung allograft tolerance. During the last funding period we have uncovered that lung-resident eosinophils, also considered a detrimental cell population for graft health, shape CD8+ T cell fate to prevent their effector differentiation. We have also described that such eosinophil-CD8+ T cell feedback loops play a crucial role in maintaining graft survival in vivo. We have further demonstrated the translational potential of this discovery and ameliorated graft rejection by altering eosinophil migration into the lung through intra-tracheal administration of chemokines. Such data provides proof of principle that mechanistic studies utilizing murine models offer the possibility for the development of lung-specific protocols for immunosuppression and tolerance induction. In project #2 we propose to decipher multiple aspects of lung allograft- specific proinflammatory loops in tolerance induction and maintenance. In aim #1 we plan to explore the interactions of IFN-γ and IL1-β in lung allograft acceptance and in aim #2 we will focus on antigen specificity in tolerance induction as well as mechanism/s mediating T cell receptor instability. In aim #3 we will focus on the role of PD-L1 in maintenance of tolerance. In addition we will explore the potential for bi-specific antibody-mediated induction of tolerance through forced interaction of eosinophils and T cells. The studies proposed here would lay the foundation for translational large animal and human work in lung allograft management in an effort to improve survival.

项目摘要/摘要使用肺移植的鼠模型的研究有助于促进我们的理解肺同种异体特异性免疫调节。与其他固体器官不同，肺部依赖于炎症反馈回路，用于建立和维持移植物接受。我们有描述的是，CD8+ T细胞长期被认为已被删除为同种异体移植的生存，请发挥作用在肺同种异体耐受性中的关键作用。在最后的资金期间，我们发现了肺居民嗜酸性粒细胞也被认为是治疗健康的有害细胞种群，形状 CD8+ T细胞命运以防止其效应子分化。我们还描述了这样的嗜酸性粒细胞-CD8+ T细胞反馈回路在维持体内移植生存中起着至关重要的作用。我们进一步证明了这一发现和改善移植物的翻译潜力通过将嗜酸性粒细胞迁移到肺部通过 - 通过迁移内给药来排斥。趋化因子。这样的数据提供了使用鼠的机理研究的原理证明模型为开发用于免疫抑制的肺特异性方案提供了可能性和耐受性诱导。在项目＃2中，我们建议破译肺部包裹的多个方面 - 耐受性诱导和维护方面的特定促炎回路。在AIM＃1中，我们计划探索IFN-γ和IL1-β在肺同种异体移植接受中的相互作用，在AIM＃2中，我们将集中精力关于耐受性诱导的抗原特异性以及机制介导T细胞接收器不稳定。在AIM＃3中，我们将专注于PD-L1在维持耐受性中的作用。此外我们将探索通过双特异性抗体介导的耐受性的潜力嗜酸性粒细胞和T细胞的强制相互作用。这里提出的研究将奠定基础用于肺同种异体管理中的翻译大型动物和人类工作，以改善生存。