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限制免疫反应中起着重要作用，保持自我公差并防止过多的附带损害。免疫检查点封锁彻底改变了癌症免疫疗法，但可能导致免疫促进事件（IRAE）。接受编程细胞的患者死亡蛋白1（PD-1）阻塞可以发展出伊拉斯，包括白癜风，结肠炎，内分泌病和西卡综合征，一种自身免疫性疾病，其特征是唾液中免疫细胞积累泪腺，导致定义和功能障碍。免疫细胞激活后，更新PD-1，并且与配体PD-L1相互作用后，PD-1信号传导导致增殖，细胞因子产生和细胞毒性。 PD-1在唾液腺的浸润淋巴细胞上表达，包括天然杀手（NK）和 T细胞。唾液腺中的低反应性免疫力被认为保留了这种精致的完整性组织，而无意中会导致病毒潜伏期。同时试图了解为什么在此器官中淋巴细胞不反应，我出乎意料地发现，PD-1的遗传丧失会导致CD8+ T细胞数量增加，并且幼稚动物唾液腺的频率。其他初步数据表明，NK细胞可能控制唾液腺中的CD8+ T细胞膨胀。基于这些数据，我假设是为了保留唾液腺的完整性，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，在特定的目标1中，我将阐明PD-1调节CD8+ T细胞的分子机制唾液腺，并表征扩展的CD8+ T细胞的转录组和效应子功能人口。在特定目标2中，我将表征CD8+ T细胞的潜在免疫病理学后果通过评估组织病理学和唾液分泌物，PD-1 KO唾液腺扩张。这些研究唾液腺免疫小球的PD-1应提供预防和治疗伊拉斯的见解。在为拟议的工作做准备，我的培训已在博士博士的杰出免疫学实验室中进行。 Laurent Brossay以及支持性病理生物学研究生课程。我的培训经验将通过参加和举办国际和国际会议，并通过我的赞助商。该提案的完成将使我为技能和关键基础做好准备成功成为独立研究人员所需的知识。