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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：
9258870
负责人：
Niroshana Anandasabapathy
金额：
$ 40.96万
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/9258870
关键词：
Address Antigens 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 In Situ In Vitro Inflammation Inflammatory Interferon Type II Lead Left 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 abstracting adaptive immunity base cell motility conditioning diphtheria toxin receptor improved in vivo in vivo Model lymph nodes macrophage monocyte novel peripheral tolerance 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.

项目总结/文摘