Immune crosstalk through shared LN drainage in the digestive system

通过消化系统中共享的 LN 引流进行免疫串扰

• 批准号: 10502682
• 负责人: Daria Esterhazy
• 金额: $ 35.43万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10502682
• 关键词: Address; Affect; Anatomy; Antigens; Attention; Autoimmune Diabetes; Automobile Driving; Back; Beta Cell; Biotin; Biotinylation; CD8-Positive T-Lymphocytes; Cells; Clone Cells; Cre driver; Cytotoxic T-Lymphocytes; Dendritic Cells; Development; Diabetes Mellitus; Diet; Digestive System Disorders; Disease; Disease Progression; Drainage procedure; Duodenum; Environment; Enzymes; Evolution; Excision; Exhibits; Exocrine pancreas; Exposure to; Failure; Flow Cytometry; Functional disorder; Gene Expression Profile; Genetic Transcription; Glucose; Goals; Hepatic; Homeostasis; Homing; Hormones; Immune; Immune System Diseases; Immune Targeting; Immune response; Immune system; Immunity; Immunologics; Infection; Inflammatory; Injury; Insulin; Insulin-Dependent Diabetes Mellitus; Intestines; Islets of Langerhans; Life; Ligase; Liver; Liver Extract; Location; Lymph; Lymph Node Drainage; Malignant neoplasm of pancreas; Mediating; Methods; Modeling; Monitor; Mus; Nature; Nutrient; Organ; Outcome; Output; Pancreas; Pancreatic Diseases; Pancreatitis; Phenotype; Positive Lymph Node; Proteins; Reaction; Regulation; Research; Route; Shapes; Site; Source; Structure of beta Cell of islet; System; T cell response; T-Lymphocyte; Testing; Therapeutic Intervention; Tissues; Tomatoes; Toxin; adaptive immunity; autoreactive T cell; autoreactivity; cellular targeting; cytotoxic; draining lymph node; enteric infection; gastrointestinal system; immunological status; imprint; insight; lymph nodes; lymphoid organ; macromolecule; man; novel; polarized cell; prevent; response; targeted treatment; uptake; virtual

PROJECT SUMMARY/ABSTRACT Hypothesis: Diseases of the pancreas are life-threatening, including pancreatic cancer (PDAC), affecting exocrine cells, and autoimmune diabetes (T1D), destroying insulin-producing β cells. External factors like infections and diet are implicated as triggers, but the disease origins remain elusive and cures are lacking. The immune system strongly contributes to disease progression, but what governs pancreatic adaptive immune tone is understudied, preventing effective immune-targeting therapy. Lymph nodes (LNs) are key sites for the initiation of tissue specific adaptive immunity, and here we hypothesize that LN sharing between pancreas and duodenum and liver influences the nature of pancreatic immunity. We postulate that both, the major lymph output from these co-drained organs and their more direct exposure to environmental perturbation, allow them to dictate LN environments, thus impacting pancreatic adaptive immune cell fate both during homeostasis and upon intestinal or hepatic insults. Finally, we propose that migratory dendritic cells (DCs) presenting pancreatic antigen are the key cellular target for such immune cross talk. This hypothesis will be tested in our Specific Aims (SA): SA #1 will characterize the phenotype of pancreatic antigen loaded DC and consequences for exocrine or endocrine pancreas specific T cell polarization in the co-drained LNs during homeostasis. SA #2 will test to what extent LN DCs and T cell fates change upon intestinal versus hepatic perturbation such as infections. SA #3 will assess the relative importance of sharing LNs with liver versus gut for the T cell landscape back in the exocrine and endocrine pancreatic tissue and, as a proof of principle, will investigate how duodenal infection, through LN sharing, affects pancreatic tissue T cells and the progression of T1D. Unique approach: 1. We will identify LN DCs loaded with pancreatic antigen by virtue of tracking tissue specific antigen biotinylation or fluorescent protein uptake. 2. We have generated novel mice that permit expression of the model antigen OVA from exocrine or endocrine pancreas, liver or gut, allowing for monitoring OVA specific T cell fate. This method permits the systematic comparison of tissue-specific T cell responses in the LNs shared with the liver versus the duodenum. Impact: This project will provide fundamental insights into how pancreatic immunity may be shaped by environmental fluctuations. While potential sources of pancreatic perturbation through LN sharing, liver and duodenum could turn out as anatomical routes for therapeutic intervention in the pancreas. Mechanistically the research will increase our understanding of DC imprinting in tissue versus LN and the impact of this “plasticity” on dictating T cell responses. More broadly, the proposal features LN sharing between organs as a previously unrecognized force shaping tissue specific immunity.

项目总结/摘要 假设：胰腺疾病危及生命，包括胰腺癌（PDAC），影响 外分泌细胞和自身免疫性糖尿病（T1 D），破坏产生胰岛素的β细胞。等外部因素 感染和饮食被认为是诱因，但疾病的起源仍然难以捉摸，而且缺乏治疗方法。的 免疫系统对疾病的进展有很大的作用，但是控制胰腺适应性免疫的是什么？ tone研究不足，阻碍了有效的免疫靶向治疗。淋巴结（LN）是淋巴结转移的关键部位。 组织特异性适应性免疫的启动，在此我们假设胰腺间LN共享 十二指肠和肝脏影响胰腺免疫的性质。我们假设，双方，主要 这些共同引流器官的淋巴输出以及它们更直接地暴露于环境扰动， 它们决定LN环境，从而影响胰腺适应性免疫细胞的命运， 以及在肠或肝损伤时。最后，我们提出，迁移性树突状细胞（DC）， 胰腺抗原是这种免疫串扰的关键细胞靶标。 这一假设将在我们的特定目标（SA）中进行检验：SA #1将表征 胰腺抗原负载DC和胰腺外分泌或内分泌特异性T细胞的后果 极化的共同引流LN在稳态。SA #2将测试LN DC和T细胞在多大程度上与IL-10结合。 在肠道与肝脏扰动如感染时，命运发生变化。SA #3将评估相对 与肝脏和肠道共享LN对于外分泌和内分泌中T细胞景观的重要性 胰腺组织，并作为一个原则的证明，将调查如何十二指肠感染，通过LN共享， 影响胰腺组织T细胞和T1 D的进展。 独特的方法：1.我们将通过追踪组织特异性表达，鉴定负载胰腺抗原的LN DC。 抗原生物素化或荧光蛋白摄取。2.我们已经培育出了能够表达 来自外分泌或内分泌胰腺、肝脏或肠道的模型抗原OVA，允许监测OVA特异性 T细胞命运。这种方法允许系统地比较淋巴结中组织特异性T细胞应答 与肝脏和十二指肠共用。 影响：该项目将提供关于胰腺免疫如何被塑造的基本见解。 环境波动。虽然通过LN共享，肝脏和胰腺扰动的潜在来源， 十二指肠可以成为胰腺中治疗性干预的解剖学路径。机械地， 研究将增加我们对组织中DC印记与LN的理解，以及这种“可塑性”的影响。 控制T细胞反应的方法更广泛地说，该提案的特点是器官之间的LN共享， 未识别的力量塑造组织特异性免疫。