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Targeting Dendritic Cell Subsets in Human Vagina to Elicit Local Immunity

靶向人类阴道中的树突状细胞亚群以引发局部免疫

基本信息

批准号：
7835184
负责人：
SangKon Oh
金额：
$ 49.99万
依托单位：
BAYLOR RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-29 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7835184
关键词：
Academic Medical Centers Address Adjuvant Antigen Targeting Antigen-Presenting Cells Antigens Area Autoimmunity B-Lymphocytes Bacteria Beds Biological Assay Biological Preservation CD8B1 gene Chlamydia Clinical Research Communicable Diseases Dendritic Cells Development Dose Employment Fc Receptor Female Flow Cytometry Funding Funding Opportunities Genital system Goals HIV Health Health Sciences Human Human Papillomavirus Humoral Immunities Hypersensitivity Immune response Immune system Immunity Immunohistochemistry Immunologic Surveillance Immunologist Immunology In Situ In Vitro Infection Institutes Knowledge Malignant Neoplasms Medicine Methods Molecular Morbidity - disease rate Mucosal Immunity Mucous Membrane Mus Occupations Physicians Prevention Preventive Public Health Research Route Scientist Secure Sexually Transmitted Diseases Simplexvirus Site Skin Software Engineering Surface System Systems Biology T-Lymphocyte Technology Testing Therapeutic Tissue Sample Tissues Training Translations Vaccination Vaccine Antigen Vaccines Vagina Work base burden of illness design in vivo insight meetings migration mortality mouse model mucosal vaccine multidisciplinary nonhuman primate novel novel strategies novel vaccines pathogen prevent programs public health relevance receptor response subcutaneous transmission process vaccine delivery vaccinology

项目摘要

DESCRIPTION (provided by applicant): This project addresses Broad Challenge Area 04-Clinical Research and Specific Challenge Topic 04-AI-101*- Develop novel methods and address key questions in mucosal immunology. Sexually transmitted diseases (STDs) cause high morbidity and mortality, and thus result in a major disease burden worldwide. New preventive vaccines against HPV have proven that protective immunity can be mounted; but challenges in curing HPV-associated cancer and other major STDs associated with HIV, HSV, Chlamydia, and other bacteria still remain. The female genital tract is a major infection site and a route for the transmission of pathogens. Therefore, vaccines that induce potent mucosal immunity in the vagina have a high potential for the prevention and treatment of STDs. The vagina is a promising site for mucosal vaccine administration. The key question is: how can we establish potent mucosal immunity against STDs in the vagina? Simply delivering vaccines to the vagina may not induce potent mucosal immunity. Dendritic cells (DCs) are major antigen presenting cells (APCs) for both cellular and humoral immunity, but different subsets of DCs have distinct functions in inducing and regulating immune responses. Thus, knowledge of the subsets of vaginal APCs will be crucial for designing mucosal vaccines that induce potent mucosal immunity in the vagina. However, the immunology of the human vagina is poorly understood. To fill the dual gaps of the lack of experts and limited knowledge, here we initiate a comprehensive study for harnessing the immunology of human vagina. This study is greatly facilitated by 1) procuring sufficient tissue samples from Baylor University Medical Center, 2) taking advantage of using the established knowledge in human skin DC subsets at the Baylor Institute for Immunology Research (BIIR), and 3) employing a systems biology approach for a comprehensive analysis of immune responses. At the end of this study, we will be able to provide knowledge in three key areas for developing mucosal vaccines against STDs: 1) The subsets of APCs that can elicit optimal quantity and quality of mucosal immunity in the vagina, 2) APC subset-specific surface receptors and activators for: a) delivering vaccines to appropriate subsets of APCs and b) activating the correct APC subsets, and 3) In situ experimental systems explored in this study will bring key insights of in vivo human immunology necessary for developing vaccines. At BIIR, we have developed a technology platform for targeting antigens directly to human DC subsets via anti-DC receptor antibody vehicles; and this work will permit informed decisions for choosing the targeting receptors and adjuvants best suited to elicit potent and sustained mucosal immunity. Importantly, this proposal fulfills the premises of the challenge funding opportunities by 1) developing novel methods and addressing key questions in human mucosal immunology, 2) generating a broad and major impact on health improvement worldwide by providing key knowledge for developing vaccines against a wide range of STD, 3) making a fundamental contribution in human immunology, and 4) preserving and creating jobs and training for highly skilled scientists. PUBLIC HEALTH RELEVANCE: This work will address the challenge in human mucosal immunology. It will have a broad impact in science and health as it will provide fundamental knowledge in the immunology of the human genital tract, particularly the vagina, which is a major site of infection and transmission of sexually-transmitted diseases (STDs). The results of this study will have immediate implications for the rational design and development of safe and effective vaccines against STDs. Importantly, this work will allow preservation and creation of jobs. 1

描述（由申请人提供）：本项目涉及广泛挑战领域04-临床研究和特定挑战主题04-AI-101*-开发新方法并解决粘膜免疫学的关键问题。性传播疾病造成高发病率和死亡率，因此在世界范围内造成重大疾病负担。针对人乳头瘤病毒的新预防疫苗已被证明可以建立保护性免疫；但在治疗hpv相关的癌症和其他与HIV、HSV、衣原体和其他细菌相关的主要性传播疾病方面仍然存在挑战。女性生殖道是主要的感染部位和病原体传播途径。因此，在阴道内诱导强效粘膜免疫的疫苗在预防和治疗性传播疾病方面具有很高的潜力。阴道是一个很有希望接种粘膜疫苗的部位。关键的问题是：我们如何在阴道内建立有效的粘膜免疫系统来对抗性病？简单地将疫苗注射到阴道内可能不会产生有效的粘膜免疫。树突状细胞（dc）是细胞免疫和体液免疫的主要抗原呈递细胞（APCs），但不同的树突状细胞亚群在诱导和调节免疫应答方面具有不同的功能。因此，了解阴道apc亚群对于设计能诱导阴道黏膜免疫的粘膜疫苗至关重要。然而，人类阴道的免疫学知之甚少。为了填补专家缺乏和知识有限的双重空白，我们在这里启动了一项利用人类阴道免疫学的综合研究。1)从贝勒大学医学中心获得足够的组织样本，2)利用贝勒免疫学研究所（BIIR）在人体皮肤DC亚群方面的既定知识，以及3)采用系统生物学方法对免疫反应进行全面分析，极大地促进了本研究。在本研究结束时，我们将能够为开发针对性传播疾病的粘膜疫苗提供三个关键领域的知识：1)能够在阴道内引发最佳数量和质量的粘膜免疫的APC亚群；2)APC亚群特异性表面受体和激活剂：a)将疫苗递送到适当的APC亚群，b)激活正确的APC亚群，以及3)本研究探索的原位实验系统将为开发疫苗提供必要的体内人类免疫学关键见解。在BIIR，我们开发了一个技术平台，通过抗DC受体抗体载体将抗原直接靶向人类DC亚群；这项工作将允许明智的决定选择最适合的靶向受体和佐剂，以引起有效和持续的粘膜免疫。重要的是，该提案满足了挑战资助机会的前提：1)开发人类粘膜免疫学的新方法和解决关键问题；2)通过为开发针对多种性病的疫苗提供关键知识，对全球健康改善产生广泛而重大的影响；3)在人类免疫学方面做出根本性贡献；4)为高技能科学家保留和创造就业机会和培训。