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.

项目摘要/摘要 假设：胰腺疾病正在威胁生命，包括胰腺癌（PDAC），影响 外分泌细胞和自身免疫性糖尿病（T1D），破坏产生胰岛素的β细胞。外部因素 感染和饮食是作为触发因素实施的，但疾病的起源仍然难以捉摸，并且缺乏治疗方法。 免疫系统强烈促进疾病的进展，但控制胰腺适应性免疫 理解了语调，以防止有效的免疫靶向疗法。淋巴结（LNS）是 启动组织特异性适应性免疫学，在这里我们假设胰腺之间的LN共享 十二指肠和肝脏会影响胰腺免疫的性质。我们假设这两个专业 这些共同排水器官及其更直接暴露于环境扰动的淋巴输出，允许 他们决定LN环境，从而影响胰腺适应性免疫鼠的命运在体内稳态期间 以及肠道或肝侮辱。最后，我们提出了迁移的树突状细胞（DC） 胰腺抗原是这种免疫交叉讲座的关键细胞靶标。 该假设将在我们的具体目的（SA）中进行检验：SA＃1将表征的表型 胰腺抗原负载的直流和内分泌或内分泌胰腺特异性T细胞的后果 稳态期间共同排水的LN的极化。 SA＃2将测试LN DC和T细胞的程度 在肠道和肝扰动（例如感染）上发生的命运发生了变化。 SA＃3将评估亲戚 与肝脏与肠道共享LN的重要性 胰组织，作为原则的证明，将研究十二指肠感染如何通过LN共享， 影响胰腺组织T细胞和T1D的进展。 独特的方法：1。我们将通过跟踪组织特异性识别带有胰腺抗原的LN DC 抗原生物素化或荧光蛋白摄取。 2。我们产生了允许表达的新小鼠 来自外分泌或内分泌胰腺，肝脏或肠道的模型抗原OVA，允许特定于OVA T细胞命运。该方法允许系统比较LNS中组织特异性T细胞反应 与肝脏与十二指肠共享。 影响：该项目将提供有关如何通过如何塑造胰腺免疫力的基本见解 环境波动。虽然通过LN共享，肝脏和 十二指肠可能会作为胰腺热干预的解剖路线。机械上 研究将增加我们对组织与LN的直流印迹以及这种“可塑性”的影响 在决定T细胞反应时。更广泛地，该提案特征是器官之间的LN共享 无法识别的力塑造组织特异性免疫。