Immunological and functional consequences triggered by the gut microbiota regulate alloimmunity and cardiac transplant outcome

肠道微生物群引发的免疫和功能后果调节同种免疫和心脏移植结果

• 批准号: 10439697
• 负责人: Jonathan S Bromberg
• 金额: $ 57.87万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10439697
• 关键词: Acute; Adoptive Cell Transfers; Affect; Alloantigen; Allogenic; Allografting; Anti-Inflammatory Agents; Antibiotic Therapy; Antibiotics; Antigens; Antiinflammatory Effect; Autoantigens; Autoimmune Diseases; B-Lymphocytes; Bacteria; Bifidobacterium; Biological Assay; Blood; Blood Vessels; Cardiac; Cell Wall; Cells; Chemical Structure; Chronic; Cicatrix; Classification; Dendritic Cells; Desulfovibrio; Diagnostic; Disease; Distal; Distant; Endothelial Cells; Epithelial; Event; FOXP3 gene; Failure; Fibrosis; Functional disorder; Genetic; Goals; Graft Survival; Heart Transplantation; Histology; Homeostasis; Human; Immune; Immune System Diseases; Immune system; Immunity; Immunohistochemistry; Immunologic Monitoring; Immunologics; Immunosuppression; In Vitro; Infection; Inflammation; Inflammatory; Innate Immune Response; Intestines; Investigation; Kidney Transplantation; Laminin; Link; Lymphatic; Lymphocyte; Lymphoid Cell; Modeling; Molecular; Monitor; Mus; Myelogenous; Myeloid Cells; Natural Immunity; Nature; Nucleic Acids; Organ; Organ Donor; Organ Preservation; Organ Transplantation; Outcome; Pathology; Pathway interactions; Pharmacology; Physiological; Population; Procedures; Property; Prophylactic treatment; Regimen; Regulatory T-Lymphocyte; Reporting; Signal Transduction; Solid; Structure; Survival Rate; T-Lymphocyte; Testing; Therapeutic immunosuppression; Transplantation; Transplantation Immunology; Work; adaptive immunity; allograft rejection; base; clinically relevant; comorbidity; diagnostic biomarker; diagnostic tool; driving force; experimental study; graft function; graft vs host disease; gut microbiota; heart allograft; host microbiota; improved; in vivo; interstitial; isoimmunity; lymph nodes; lymphocyte trafficking; macrophage; microbial; microbiota; migration; mouse model; novel; novel strategies; receptor; response; success; systemic inflammatory response; therapeutic target; trafficking; transplant model; transplantation medicine; vascular inflammation

Project Summary Many aspects of the innate and adaptive immunity are critically regulated by the microbiota. Microbial cells, their metabolites and nucleic acids engage various immune cells, resulting in pro- or anti-inflammatory signals that differ based on chemical structures, cellular receptors, and physiological context. The microbiota not only influences local immunity, but also has distant effects on systemic immunity. Local microbiota stimulation of innate and adaptive immune cells results in those cells or their products to migrate or traffic through lymphatics or blood, and influence diseases. However, the precise causal pathways linking microbiota components to immune cells and downstream effectors in most cases remain to be defined. Solid organ transplantation has made significant progress over the past 35 years and has become a routine procedure. Cardiac transplantation is a common and successful transplant, with graft survival after one year exceeding 80-90%. Despite advances in all aspects of allografting, the rate of decline of cardiac and other graft function beyond the first year after transplant has not changed in over 20 years. All allografts eventually succumb to chronic vascular, interstitial or epithelial changes. Despite critical improvements in immunosuppressive regimens, immunologic monitoring, and molecular classification of organ pathology, chronic rejection still persists and its primary cause is not understood. Prior work has focused on distal events of fibrosis and inflammation, but not on proximal causes of inflammation and immunity. We previously showed in renal transplantation, large and persistent shifts in the composition and complexity of the gut microbiota as a result of immunosuppression and antibiotics. Such shifts in the microbiota are indicative of all organ transplants, including cardiac transplants. We therefore hypothesized that these changes could critically affect graft outcome. Our current studies dissected the interactions between the enteric microbiota and innate and adaptive immunity, in clinically-relevant cardiac transplantation models of acute and chronic rejection. Our results show that both pro-inflammatory and anti-inflammatory microbiota populations, as well as single bacteria, can be defined by their effects on the long-term outcome of the grafts. Mechanistic explorations suggest a differential stimulation of myeloid cells (i.e. macrophages and DC), resulting in changes in LN structure that influence allogeneic immunity. Thus, we hypothesize that the microbiota directly regulates innate immunity, which in turn regulates systemic inflammation and adaptive immunity, thereby determining the occurrence and progression of graft fibrosis, inflammation and graft survival. To investigate this hypothesis, we will take advantage of our expertise in microbiota analysis and in molecular and cellular transplant immunology. The definition of pro-inflammatory and anti-inflammatory microbiota and strains may provide a precise platform to define the most important upstream influences that initiate organ inflammation and scarring and could serve as potent diagnostic markers for allograft management.

项目摘要 先天免疫和适应性免疫的许多方面都受到微生物群的严格调节。微生物 细胞、其代谢物和核酸参与各种免疫细胞，导致促炎或抗炎作用。 基于化学结构、细胞受体和生理环境而不同的信号。微生物群 不仅影响局部免疫，而且对全身免疫也有远期影响。本地微生物群 刺激先天性和适应性免疫细胞导致这些细胞或其产物迁移或运输 通过药物或血液，影响疾病。然而，连接微生物群的精确因果途径 在大多数情况下，免疫细胞和下游效应物的组分仍有待确定。 实体器官移植在过去的35年里取得了重大进展， 例行程序心脏移植是一种常见而成功的移植手术， 年超过80- 90%。尽管在同种异体移植的各个方面都取得了进展，但心脏和其他器官移植的下降率仍然很低。 移植后第一年以后的移植物功能在20多年来没有改变。所有同种异体移植物最终 死于慢性血管、间质或上皮变化。尽管取得了重大进展， 免疫抑制方案、免疫学监测和器官病理学的分子分类， 慢性排斥仍然存在，其主要原因尚不清楚。以前的工作集中在远端事件 但对炎症和免疫的近端原因没有影响。 我们以前在肾移植中发现，在组成上有大的和持续的变化， 免疫抑制和抗生素导致肠道微生物群的复杂性。这种微生物群的变化 是所有器官移植的标志包括心脏移植因此，我们假设这些 这些变化会严重影响移植物的结果。我们目前的研究剖析了肠道之间的相互作用， 微生物群和先天性和适应性免疫，在临床相关的心脏移植模型的急性和 慢性排斥我们的研究结果表明，促炎和抗炎微生物群， 以及单个细菌，可以通过它们对移植物的长期结果的影响来定义。机械论 研究表明，骨髓细胞（即巨噬细胞和DC）的差异刺激，导致变化 影响同种异体免疫LN结构。因此，我们假设微生物群直接调节 先天免疫，这反过来又调节全身炎症和适应性免疫，从而决定了 移植物纤维化、炎症和移植物存活的发生和进展。为了研究这个假设，我们 将利用我们在微生物群分析以及分子和细胞移植方面的专业知识， 免疫学促炎性和抗炎性微生物群和菌株的定义可以提供 一个精确的平台来定义启动器官炎症和瘢痕形成的最重要的上游影响 并且可以作为同种异体移植管理的有效诊断标记。