PD-1 Mediated Regulation of Salivary Gland Integrity

PD-1 介导的唾液腺完整性调节

基本信息

批准号：
10751477
负责人：
Samantha Borys
金额：
$ 4.85万
依托单位：
BROWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10751477
关键词：
Acceleration Animals Autoantibodies Autoimmune Diseases Autoimmunity B-Lymphocytes Biological Markers CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cell Count Cells Chronic Colitis Collaborations Cytomegalovirus Cytomegalovirus Infections Data Deglutition Denture Wear Deterioration Disease Dry Eye Syndromes Dryness Esthesia Exhibits Exocrine Glands Frequencies Functional disorder Genetic Gland Histopathology Human Immune Immune response Immune system Immunology Immunotherapeutic agent In Situ Infection Infiltration Inflammation International Knockout Mice Knowledge Laboratories Lacrimal gland structure Life Ligands Lip structure Lymphocyte Malignant Neoplasms Measurement Measures Mediating Mentors Modeling Molecular Murid herpesvirus 1 Natural Killer Cells Organ Pathogenesis Pathologic Pathology Patients Play Population Preparation Prevention Production Proliferating Quality of life Regulation Research Research Personnel Rheumatism Risk Factors Role Saliva Salivary Salivary Glands Self Tolerance Seroprevalences Signal Transduction Sjogren&apos s Syndrome Sorting Symptoms Syndrome T-Cell Proliferation T-Lymphocyte T-Lymphocyte Subsets Taste Perception Therapeutic Tissues Training Virus Virus Diseases Virus Latency Vitiligo Woman Work Xerostomia anti-PD-1 autoreactivity cancer immunotherapy career chronic infection cytokine cytotoxicity experience eye dryness immune activation immune checkpoint immune checkpoint blockade immune-related adverse events immunopathology insight irritation mouse model preservation prevent programmed cell death ligand 1 programmed cell death protein 1 programs receptor restraint saliva secretion single cell analysis single cell sequencing skills symposium transcriptome tumor viral transmission

项目摘要

Abstract Immune checkpoints play an important role in restraining the immune response, maintaining self- tolerance and preventing excessive collateral damage. Immune checkpoint blockade has revolutionized cancer immunotherapy but can lead to immune related adverse events (IrAEs). Patients receiving programmed cell death protein 1 (PD-1) blockade can develop IrAEs including vitiligo, colitis, endocrinopathies, and Sicca Syndrome, an autoimmune disease characterized by the accumulation of immune cells in the salivary and lacrimal glands, leading to deterioration and dysfunction. After immune cell activation, PD-1 is upregulated, and upon interacting with its ligand PD-L1, PD-1 signaling results in reduced proliferation, cytokine production, and cytotoxicity. PD-1 is expressed on infiltrating lymphocytes of the salivary gland including natural killer (NK) and T cells. Hyporesponsive immune cells in the salivary gland are thought to retain the integrity of this delicate tissue, while inadvertently contributing to viral latency. While trying to understand why lymphocytes in this organ are hyporesponsive, I unexpectedly found that genetic loss of PD-1 results in increased CD8+ T cell number and frequency in the salivary glands of naïve animals. Additional preliminary data suggests that NK cells may control CD8+ T cell expansion in the salivary gland. Based on these data, I hypothesize that in order to preserve the integrity of the salivary gland, NK cells may control T cell proliferation via the PD-1/PD-L1 axis in this organ. Therefore, in Specific Aim 1, I will elucidate the molecular mechanism by which PD-1 regulates CD8+ T cells in the salivary gland, and characterize the transcriptome and effector functions of the expanded CD8+ T cell population. In Specific Aim 2, I will characterize the potential immunopathological consequences of CD8+ T cell expansion in the PD-1 KO salivary gland by assessing histopathology and saliva secretions. These studies of PD-1 on salivary gland immune cells should provide insights for prevention and treatments of IrAEs. In preparation for the proposed work, my training has taken place in the outstanding immunology laboratory of Dr. Laurent Brossay, as well as within the supportive Pathobiology Graduate Program. My training experience will be enriched by attending and presenting at national and international conferences, and thoughtful mentoring by my sponsor. Completion of this proposal will prepare me with a repertoire of skills and the key foundational knowledge required for a successful career as an independent researcher.

抽象的免疫检查点在抑制免疫反应、维持自身免疫功能等方面发挥着重要作用。耐受性和防止过度的附带损害已经彻底改变了癌症。免疫疗法，但可能导致接受程序化细胞治疗的患者出现免疫相关不良事件 (IrAE)。死亡蛋白 1 (PD-1) 阻断可导致 IrAE，包括白癜风、结肠炎、内分泌病和干燥症综合症，一种自身免疫性疾病，其特征是免疫细胞在唾液和唾液中积聚泪腺，导致免疫细胞激活后恶化和功能障碍，PD-1上调，并且在与其配体 PD-L1 相互作用后，PD-1 信号传导会导致增殖、细胞因子产生减少， PD-1 在唾液腺浸润淋巴细胞上表达，包括自然杀伤细胞 (NK) 和唾液腺中反应低下的免疫细胞被认为保留了这种脆弱的完整性。组织，同时无意中导致了病毒潜伏期，同时试图了解为什么淋巴细胞会出现在这个器官中。反应低下，我意外地发现 PD-1 基因缺失会导致 CD8+ T 细胞数量增加，额外的初步数据表明 NK 细胞可能控制着幼稚动物的唾液腺中的频率。基于这些数据，我认为这是为了保存唾液腺中的 CD8+ T 细胞。 NK 细胞可以通过该器官中的 PD-1/PD-L1 轴控制 T 细胞增殖。因此，在具体目标1中，我将阐明PD-1在体内调节CD8+ T细胞的分子机制。唾液腺，并表征扩增的 CD8+ T 细胞的转录组和效应器功能在具体目标 2 中，我将描述 CD8+ T 细胞的潜在免疫病理学后果。这些研究通过评估组织病理学和唾液分泌来确定 PD-1 KO 唾液腺的扩增。唾液腺免疫细胞上的 PD-1 应该为 IrAE 的预防和治疗提供见解。为了准备拟议的工作，我的培训是在 Dr. 杰出的免疫学实验室进行的。劳伦特·布罗赛（Laurent Brossay）以及支持性病理生物学研究生计划中的培训经验将。通过参加国内和国际会议并在会上发表演讲，以及通过深思熟虑的指导来丰富自己的知识我的赞助商完成此提案将为我提供一系列技能和关键基础知识。作为一名独立研究人员取得成功职业生涯所需的知识。