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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）：该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中的关键问题。性传播疾病（性病）造成高发病率和高死亡率，从而在全世界造成重大疾病负担。针对HPV的新预防性疫苗已经证明可以安装保护性免疫;但在治疗HPV相关癌症和与HIV，HSV，衣原体和其他细菌相关的其他主要性病方面仍然存在挑战。女性生殖道是主要的感染部位，也是病原体传播的途径。因此，在阴道中诱导有效粘膜免疫的疫苗对于预防和治疗性病具有很高的潜力。阴道是粘膜疫苗给药的一个有希望的部位。关键问题是：我们如何在阴道内建立有效的粘膜免疫来对抗性病？简单地将疫苗递送到阴道可能不会诱导有效的粘膜免疫。树突状细胞（DCs）是细胞免疫和体液免疫的主要抗原递呈细胞（APC），但不同亚群的DCs在诱导和调节免疫反应方面具有不同的功能。因此，阴道APC的亚群的知识将是至关重要的粘膜疫苗，诱导有效的粘膜免疫阴道。然而，人类阴道的免疫学知之甚少。为了填补缺乏专家和知识有限的双重空白，在这里，我们发起了一个全面的研究，利用人类阴道的免疫学。本研究通过以下方式大大促进：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）在人类皮肤DC亚群中的既定知识，以及3）采用系统生物学方法对免疫应答进行全面分析。在本研究结束时，我们将能够提供三个关键领域的知识，用于开发针对性病的粘膜疫苗：1）可以在阴道中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）将疫苗递送至合适的APC亚群，和B）激活正确的APC亚群，和3）本研究中探索的原位实验系统将带来开发疫苗所需的体内人类免疫学的关键见解。在BIIR，我们已经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DC亚群;这项工作将允许明智的决定，选择最适合引发有效和持续的粘膜免疫的靶向受体和佐剂。重要的是，该提案通过以下方式满足了挑战资助机会的前提：1）开发新方法并解决人类粘膜免疫学中的关键问题，2）通过为开发针对各种STD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）在人类免疫学中做出根本性的贡献，（4）保留和创造就业机会，培训高技能科学家。公共卫生相关性：这项工作将解决人类粘膜免疫学的挑战。它将对科学和健康产生广泛的影响，因为它将提供人类生殖道免疫学的基本知识，特别是阴道，这是性传播疾病（性病）感染和传播的主要场所。这项研究的结果将对合理设计和开发安全有效的性病疫苗产生直接影响。重要的是，这项工作将有助于保留和创造就业机会。1