MUCOSAL AND SYSTEMIC IMMUNITY IN HUMAN SHIGELLA VACCINES

人类志贺氏菌疫苗的粘膜和系统免疫

• 批准号: 2757768
• 负责人: Marcelo B. Sztein
• 金额: $ 18.98万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-03-01 至 2001-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2757768
• 关键词: Shigella vaccines; T cell receptor; active immunization; bacterial antigens; cellular immunity; clinical research; cytokine; cytotoxic T lymphocyte; drug screening /evaluation; enzyme linked immunosorbent assay; flow cytometry; human subject; luminescence; mucosal immunity; polymerase chain reaction; tissue /cell culture

The success of vaccines depends upon the induction of strong, long lasting immune responses that will protect the individual from a subsequent encounter with the infectious agent. Epidemiologic evidence and results of clinical trials suggests that the development of an effective vaccine against Shigella is an achievable goal. Adult volunteers who were experimentally infected with either wild type S. sonnei or S. flexneri 2a at the CVD were significantly protected against illness following rechallenge with the homologous strain. However, the presence of antibodies to Shigella measured in these volunteers did not correlate with resistance to shigellosis following challenge. Cell-mediated immunity (CMI) is a key effector mechanism involved in protection against many intracellular pathogens, including bacteria. However, very limited information is available concerning the role of CMI in Shigella infection. The overall goal of the proposed studies is to identify the immunological mechanisms that mediate effective protection from shigellosis following vaccination and natural infection with Shigella. Our hypothesis is that CMI responses play a central role in protection of volunteers from shigellosis following infection with wild-type Shigella and live Shigella vaccine candidates. The identification of CMI that correlate with protection following exposure to wild-type Shigella will greatly enhance our understanding of the mechanisms underlying protection in shigellosis and the development of Shigella vaccines. Specifically, using cells isolated from mucosal biopsies and peripheral blood mononuclear cells (PBMC) obtained from volunteers immunized with wild-type or attenuated strains of S. flexneri 2a, S. dysenteriae and S. sonnei we propose to test the following hypotheses: (1) Challenge with wild-type Shigella or immunization with Shigella vaccine candidates elicits the appearance in circulation of specific cytotoxic T lymphocytes (CTL); (2) Challenge with wild-type Shigella or immunization with attenuated strains of Shigella elicits the appearance in circulation of specific T lymphocytes that proliferate and produce interferon-gamma interferon-gamma (IFN-gamma), as well as other "type-1" cytokines, in response to Shigella antigens, (3) Challenge with wild-type Shigella or immunization with attenuated strains of Shigella elicits the appearance in the gut mucosa of specific CTL effectors and T lymphocytes that proliferate and produce IFN- gamma, as well as other "type-1" cytokines, in response to Shigella antigens; (4) CTL responses and/or IFN-gamma production elicited by immunization at the mucosal and systemic levels correlate with protection to challenge with virulent Shigella strains; and (5) Determine whether "protective epitopes" can be identified in Shigella antigens.

疫苗的成功取决于诱导强烈、持久的免疫应答，这种免疫应答将保护个体免受随后与感染原的接触。流行病学证据和临床试验结果表明，开发一种有效的志贺氏菌疫苗是一个可以实现的目标。 实验感染野生型S的成年志愿者。sonnei或S.在用同源菌株再攻击后，CVD处的福氏2a显著保护免于疾病。然而，在这些志愿者中测得的志贺氏菌抗体的存在与挑战后对志贺氏菌病的耐药性无关。细胞介导的免疫（CMI）是一个关键的效应机制，涉及对许多细胞内病原体，包括细菌的保护。 然而，关于CMI在志贺氏菌感染中的作用的信息非常有限。 拟议研究的总体目标是确定介导疫苗接种和自然感染志贺氏菌后有效预防志贺氏菌病的免疫机制。 我们的假设是，CMI反应在保护志愿者感染野生型志贺氏菌和志贺氏菌活疫苗后免受志贺氏菌感染方面发挥着核心作用。鉴定与暴露于野生型志贺菌后的保护相关的CMI将极大地增强我们对志贺菌病保护机制和志贺菌疫苗开发的理解。具体而言，使用从粘膜活检分离的细胞和从用野生型或减毒的S. flexneri 2a，S.和S. Sonnei提出了以下假设：（1）用野生型志贺菌攻击或用志贺菌候选疫苗免疫可引起循环中特异性细胞毒性T淋巴细胞（CTL）的出现;（2）用野生型志贺氏菌攻击或用志贺氏菌减毒株免疫可使循环中出现增殖并产生干扰素-γ的特异性T淋巴细胞（3）用野生型志贺氏菌攻击或用志贺氏菌减毒株免疫可促使肠粘膜中出现特异性CTL效应子和T淋巴细胞，其增殖并产生IFN-γ以及其它“1型”细胞因子，以响应志贺氏菌抗原;（4）粘膜和全身水平的免疫诱导的CTL应答和/或IFN-γ产生与对毒性志贺氏菌菌株攻击的保护相关;和（5）确定是否可以在志贺氏菌抗原中鉴定“保护性表位”。