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

项目摘要 先天免疫和获得性免疫的许多方面都受到微生物区系的严格调控。微生物 细胞、其代谢产物和核酸与各种免疫细胞相互作用，从而产生促炎或抗炎作用。 根据化学结构、细胞受体和生理环境而不同的信号。微生物区系 不仅影响局部免疫，对全身免疫也有较远的影响。本地微生物区系 先天免疫细胞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，并影响疾病。然而，连接微生物区系的确切因果路径 在大多数情况下，免疫细胞和下游效应器的成分仍有待定义。 实体器官移植在过去的35年里取得了重大进展，已经成为一种 例行程序。心脏移植是一种常见且成功的移植，移植物一次又一次存活。 超过80%-90%的年份。尽管在同种异体移植的各个方面都取得了进展，但心脏和其他器官的下降速度 移植后第一年以后的移植物功能在20多年里没有改变。最终所有的同种异体移植 屈从于慢性血管、间质或上皮性病变。尽管有重大改进，但 免疫抑制疗法、免疫学监测和器官病理的分子分类， 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上 关于纤维化和炎症，但不是关于炎症和免疫的近端原因。 我们之前在肾移植中显示，成分和 免疫抑制和抗生素导致的肠道微生物区系的复杂性。微生物区系的这种转变 表明所有器官移植，包括心脏移植。因此，我们假设这些 这些变化可能会严重影响移植的结果。我们目前的研究解剖了肠道之间的相互作用 临床相关急性和慢性心脏移植模型中的微生物区系与先天免疫和获得性免疫 慢性排斥。我们的结果表明，无论是促炎还是抗炎微生物群，AS 和单个细菌一样，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，髓系细胞(即巨噬细胞和DC)受到不同的刺激，导致改变 在影响同种异体免疫的LN结构中。因此，我们假设微生物区系直接调节 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发展。为了研究这一假设，我们 将利用我们在微生物区系分析以及分子和细胞移植方面的专业知识 免疫学。促炎和抗炎微生物区系和菌株的定义可以提供 精确的平台来定义引发器官炎症和疤痕形成的最重要的上游影响 可作为同种异体肾移植治疗的有效诊断标志物。

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.