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: 9975884
• 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 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9975884
• 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; Epithelium; 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; Immunology; 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; Work; adaptive immunity; allograft rejection; base; clinically relevant; comorbidity; diagnostic biomarker; driving force; experimental study; graft function; graft vs host disease; gut microbiota; heart allograft; host microbiota; improved; in vivo; interstitial; isoimmunity; lymph nodes; macrophage; microbial; microbiota; migration; mouse model; novel; novel strategies; receptor; response; success; therapeutic target; tool; 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.

项目概要 先天性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、其代谢物和核酸与各种免疫细胞结合，产生促炎或抗炎作用 根据化学结构、细胞受体和生理背景而不同的信号。微生物群 不仅影响局部免疫，还对全身免疫产生远距离影响。当地微生物群 先天性和适应性免疫细胞的刺激导致这些细胞或其产物迁移或运输 通过淋巴管或血液，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，免疫细胞的组成部分和下游效应器仍有待定义。 实体器官移植35年来取得了重大进展，已成为 常规程序。心脏移植是一种常见且成功的移植手术，移植后移植物成活 年超过80-90%。尽管同种异体移植的各个方面都取得了进步，但心脏和其他疾病的下降率 移植后第一年之后的移植物功能在 20 多年来没有发生变化。最终所有同种异体移植 屈服于慢性血管、间质或上皮变化。尽管有重大改进 免疫抑制方案、免疫监测和器官病理学分子分类， 慢性排斥反应仍然存在，其主要原因尚不清楚。之前的工作主要集中在远端事件 纤维化和炎症的影响，但不是炎症和免疫的近端原因。 我们之前在肾移植中发现，成分和成分发生了大而持续的变化。 免疫抑制和抗生素导致肠道微生物群变得复杂。微生物群的这种变化 表示所有器官移植，包括心脏移植。因此我们假设这些 变化可能严重影响移植结果。我们目前的研究剖析了肠溶之间的相互作用 微生物群与先天性和适应性免疫在临床相关的急性和慢性心脏移植模型中的作用 慢性排斥反应。我们的结果表明，促炎和抗炎微生物群， 以及单一细菌，可以通过它们对移植物长期结果的影响来定义。机械论 探索表明骨髓细胞（即巨噬细胞和 DC）的差异刺激，导致变化 影响同种异体免疫的 LN 结构。因此，我们假设微生物群直接调节 先天免疫，进而调节全身炎症和适应性免疫，从而决定 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。促炎和抗炎微生物群和菌株的定义可能提供 精确的平台来定义引发器官炎症和疤痕的最重要的上游影响 并可以作为同种异体移植管理的有效诊断标志物。