Targeting Dendritic Cell Subsets in Human Vagina to Elicit Local Immunity

描述(由申请者提供)：这个项目涉及广泛的挑战领域04-临床研究和特殊挑战主题04-AI-101*-开发新的方法和解决粘膜免疫学的关键问题。性传播疾病(STDS)导致高发病率和高死亡率，从而造成世界范围内的重大疾病负担。针对HPV的新的预防性疫苗已经证明可以提高保护性免疫；但在治疗HPV相关癌症和与艾滋病毒、单纯疱疹病毒、衣原体和其他细菌相关的其他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，也是病原体传播的途径。因此，在阴道内诱导强大的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的粘膜疫苗接种部位。关键的问题是：我们如何才能建立有效的粘膜免疫力，以防阴道中的性传播疾病？简单地将疫苗接种到阴道可能不会诱导强大的粘膜免疫力。树突状细胞(DC)是细胞免疫和体液免疫的主要抗原提呈细胞，但不同亚群的DC在诱导和调节免疫反应中具有不同的功能。因此，对阴道APC亚群的了解对于设计在阴道内诱导强大的粘膜免疫的粘膜疫苗至关重要。然而，人们对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，我们在这里启动了一项利用人类阴道免疫学的全面研究。这项研究在很大程度上得益于1)从贝勒大学医学中心获取足够的组织样本，2)利用贝勒免疫研究所(BIIR)在人类皮肤DC亚群中已建立的知识，以及3)使用系统生物学方法对免疫反应进行全面分析。在这项研究结束时，我们将能够在三个关键领域提供知识，以开发针对STD的黏膜疫苗：1)能够在阴道内诱导最佳数量和质量的粘膜免疫的APC亚群，2)APC亚群特异的表面受体和激活剂，用于：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，我们开发了一个通过抗DC受体抗体载体将抗原直接靶向人类DC亚群的技术平台；这项工作将使我们能够在知情的情况下做出决定，选择最适合诱导有效和持续的粘膜免疫的靶向受体和佐剂。重要的是，这项提议通过1)开发新方法和解决人类黏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，对世界各地的健康改善产生广泛和重大的影响，3)在人类免疫学方面做出根本贡献，以及4)保持和创造高技能科学家的就业和培训，从而满足了挑战资助机会的前提。 公共卫生相关性：这项工作将解决人类黏膜免疫学方面的挑战。它将对科学和卫生产生广泛影响，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(STDS)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具有直接的意义。重要的是，这项工作将允许保留和创造就业机会。1

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