Systemic immunoregulatory consequences of bacterial translocation during health and disease

健康和疾病期间细菌易位的全身免疫调节后果

基本信息

  • 批准号:
    10339088
  • 负责人:
  • 金额:
    $ 45.33万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-09-21 至 2026-06-30
  • 项目状态:
    未结题

项目摘要

Autoimmune hepatitis (AIH) is a chronic, progressive, auto-inflammatory liver disorder that often becomes refractory to immunosuppressants-the sole therapeutic option for AIH patients. Hepatic inflammation, which sets the stage for overt AIH, is considered the main driver of hepatic tissue damage and fibrosis. While reversible, in the absence of treatment AIH progresses to cirrhosis and end stage liver disease, requiring liver transplantation in around 10% of cases. Its exact trigger and the underlying mechanisms by which AIH develops are poorly understood, although genetic and environmental factors play an important role. The local liver microbiome has been identified as one critical environmental factor that modulates hepatic pathology. The expansion of commensal bacteria such as Lactobacilli spp. within the liver is associated with an increased severity of experimental liver pathology, and Lactobacilli spp. are enriched in livers of AIH patients. Our lab recently published that Lactobacillus reuteri (L. reuteri) translocates to internal tissues and thereby drives systemic inflammation in mice that lack the epigenetic regulator Tet methylcytosine dioxygenase 2 (Tet2) in hematopoietic cells (Tet2VAV mice). We recently found that such mice have AIH and are a model system to study this disease, supported by epidemiological evidence that TET2 deficient individuals display cardinal features of liver disease. The pathogenetic mechanisms underlying AIH, and in particular how the liver microbiome may drive it, are unclear. Interferon- γ (IFN-γ) producing TCR CD8 T cells (Tc1 cells) have been identified to play an essential role in AIH. Missing is an understanding of the key signals from the liver microbiota and how they are linked to the induction of such pathogenic cells. Intriguingly, L. reuteri efficiently catabolizes dietary tryptophan (Trp) to the aryl hydrocarbon receptor (AhR) agonist indole-3-carbinol (I3C). In a lupus model, AhR ligands derived from E. gallinarum promoted Th17-driven autoimmunity. Here, based on our new data and this context from the literature, we propose a model and testable hypothesis explaining how L. reuteri promotes AIH. We will test our central hypothesis that L. reuteri promotes hepatic Tc1 cell immunity by releasing I3C and/or by fueling L. reuteri- specific Tc1 cells in two independent models of AIH (Tet2VAV mice and Concanavalin A-mediated hepatitis). Furthermore, we posit that therapeutic approaches that suppress AhR signaling protect from L. reuteri-triggered Tc1 cell mediated AIH-like pathology. We will investigate this hypothesis in three specific aims. In Aim 1 we will determine whether L. reuteri derived I3C acts directly on CD8 T cells via AhR, which promotes Tc1 cell effector function that drives AIH-like pathology. In Aim 2 we will define whether L. reuteri-specific CD8 T cells drive AIH- like disease. In Aim 3 we will define therapeutic approaches targeting AhR signaling within CD8 T cells (dietary Trp, AhR blockade) in protecting from AIH-like pathology. These aims will lead to a better understanding of the pathophysiology of AIH and assess rationale therapeutic interventions for patients with AIH.
自身免疫性肝炎(AIH)是一种慢性、进行性、自身炎症性肝脏疾病,通常会发展为

项目成果

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Marlies Meisel其他文献

Marlies Meisel的其他文献

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{{ truncateString('Marlies Meisel', 18)}}的其他基金

Role of probiotic Lactobacillus reuteri in orchestrating systemic anti-tumor immunity
益生菌罗伊氏乳杆菌在协调全身抗肿瘤免疫中的作用
  • 批准号:
    10586109
  • 财政年份:
    2022
  • 资助金额:
    $ 45.33万
  • 项目类别:
Role of probiotic Lactobacillus reuteri in orchestrating systemic anti-tumor immunity
益生菌罗伊氏乳杆菌在协调全身抗肿瘤免疫中的作用
  • 批准号:
    10417677
  • 财政年份:
    2022
  • 资助金额:
    $ 45.33万
  • 项目类别:
Systemic immunoregulatory consequences of bacterial translocation during health and disease
健康和疾病期间细菌易位的全身免疫调节后果
  • 批准号:
    10661820
  • 财政年份:
    2021
  • 资助金额:
    $ 45.33万
  • 项目类别:
Systemic immunoregulatory consequences of bacterial translocation during health and disease
健康和疾病期间细菌易位的全身免疫调节后果
  • 批准号:
    10490451
  • 财政年份:
    2021
  • 资助金额:
    $ 45.33万
  • 项目类别:

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