Peripheral mechanisms of homeostasis and tolerance through skin dendritic cells

通过皮肤树突状细胞实现稳态和耐受的外周机制

基本信息

批准号：
9397655
负责人：
Niroshana Anandasabapathy
金额：
$ 5.59万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-19 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9397655
关键词：
Address Autoantigens Autoimmune Diseases Autoimmunity B-Lymphocytes Blood Cancer Vaccines Cells Clinic Colorectal Cancer Cues Cutaneous Cutaneous Melanoma Data Dendritic Cells Dendritic cell activation Deposition Detection Development Emigrant Feedback Gene Expression Genes Genetic Glomerulonephritis Goals Growth Hematopoietic Homeostasis Human IFNGR1 gene Immune Immune Tolerance Immune system Immunity Immunologic Surveillance Immunology Immunotherapy Impairment In Situ In Vitro Inflammation Inflammatory Injectable Interferon Type II Lead Lung Lymphoid Tissue Malignant Neoplasms Malignant neoplasm of lung Modality Modeling Mus PDCD1LG1 gene Pathway interactions Patients Peripheral Population Property Regulation Regulatory T-Lymphocyte Reporting Role Science Screening for Skin Cancer Seeds Self Tolerance Sentinel Skin Skin Cancer Surveys T-Lymphocyte Testing Therapeutic Intervention Tissues Transcript Travel Tumor Escape adaptive immunity base cell motility conditioning diphtheria toxin receptor improved in vivo in vivo Model lymph nodes macrophage monocyte novel peripheral tolerance permissiveness programs skin disorder therapeutic target tool trafficking tumor tumor progression

项目摘要

Project Summary/Abstract The immune system surveys the skin and other barrier tissues such as lung and gut, but mechanisms for failed immunity in the periphery that lead to cancer or autoimmune diseases are unknown. The dendritic cell (DC) is a specialized immune sentinel that directs T cells to tolerance or immunity. DC comprise a rich network in skin consisting of several different populations, but are understudied, leaving a major gap in therapeutic intervention. We have identified distinct properties for DC in skin that relay information by migrating out to the draining lymph node (LN). We find during inflammation skin migratory DC may direct T cells to tolerance by unknown mechanisms, counter-regulating and controlling immunity. These cells are uniquely genetically programed in humans and in mouse to dampen immunity with a high expression of shared tolerance genes, including some genes such as PD-L1 that have been successfully targeted in the clinic for peripheral tissue cancers including melanoma skin cancer, colorectal cancer and lung cancer. We hypothesize homeostatic programming of skin DC leads to failed immune priming leading to impaired early detection of skin cancers. We find these pathways are of great importance as therapeutic targets to promote self-tolerance (such as during autoimmune disease) or to block tolerance (to improve immunity during cancer). Because these mechanisms are distinct they can be combined with current modalities for patients in immunotherapy of skin cancer, vaccine science, and inflammatory skin disease. In 2 discrete aims, this application will address programmatic conditioning of skin DCs and the unique cellular mechanisms by which they promote immune tolerance in both mice and humans, examining consequences during immune priming and early skin cancer growth.

项目摘要/摘要免疫系统调查皮肤和其他屏障组织，例如肺和肠道，但导致癌症或自身免疫性疾病的周围免疫力失败的机制是未知的。树突状细胞（DC）是一种专门的免疫前哨，将T细胞引导到耐受性或免疫力。 DC包括一个丰富的皮肤网络，由几种不同人群，但被研究不足，在治疗干预方面留下了重大差距。我们有通过迁移到排水，可以确定皮肤中直流的不同特性淋巴结（LN）。我们发现在炎症期间，皮肤迁移DC可能会将T细胞引导到耐受性通过未知机制，对免疫进行反调节和控制。这些细胞是独特的在人类和小鼠中通过遗传编程以高表达衰减免疫力共享耐受性基因，包括一些成功的基因，例如PD-L1 针对诊所中的周围组织癌症，包括黑色素瘤皮肤癌，结直肠癌癌症和肺癌。我们假设皮肤直流的稳态编程导致失败免疫启动导致皮肤癌的早期发现受损。我们发现这些途径是作为促进自我耐受性的治疗目标，非常重要（例如自身免疫性疾病）或阻止耐受性（以提高癌症的免疫力）。因为这些机制是不同的皮肤癌，疫苗科学和炎症性皮肤病的免疫疗法。在2个离散目的，此应用程序将解决皮肤DC和独特的蜂窝的编程条件它们促进小鼠和人类免疫耐受性的机制，检查免疫启动和皮肤早期癌症生长期间的后果。