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: 9795098
• 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/9795098
• 关键词: Acute; Adoptive Cell Transfers; Affect; Alloantigen; Allogenic; Allografting; Anti-inflammatory; 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; Comorbidity; 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; Immunology; Immunosuppression; Immunosuppressive Agents; 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; 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.

项目总结