Clostridium difficile Immunity: Role of IGA and GALT

艰难梭菌免疫：IGA 和 GALT 的作用

• 批准号: 9068835
• 负责人: Margaret E. Conner
• 金额: $ 19.81万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-15 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9068835
• 关键词: Address; Adjuvant; Age; Antibiotic Therapy; Antibodies; Antibody Response; Antigens; B-Lymphocytes; CCR9 gene; Cessation of life; Clostridium difficile; Colon; Cytomegalovirus Infections; Defense Mechanisms; Dendritic Cells; Development; Diarrhea; Disease; Enterotoxins; Failure; Gastrointestinal tract structure; Goals; Gut associated lymphoid tissue; Health; Healthcare; Homing; Hospitalization; Human; Immune response; Immunity; Immunoglobulin A; Immunoglobulin Class Switching; Immunoglobulin G; Immunoglobulin-Secreting Cells; Immunology; Immunosuppression; Infection; Intestines; Lamina Propria; Lymphoid Follicle; Lymphoid Tissue; Maintenance; Mediating; Memory; Modeling; Monoclonal Antibodies; Pathway interactions; Patients; Positioning Attribute; Predisposition; Primary Infection; Production; Recurrence; Recurrent disease; Risk Factors; Role; Serum; Site; Therapeutic; Time; Toxin; Tretinoin; United States; Vaccine Design; Vaccines; Vitamin A; Work; burden of illness; care burden; chemokine; cost; design; enteric pathogen; gastrointestinal; innovation; insight; integrin alpha4beta7; mortality; neutralizing antibody; novel; novel strategies; pathogen; receptor; relapse risk; response; targeted treatment; treatment strategy; vaccine candidate; vaccine development; vaccine-induced immunity

DESCRIPTION (provided by applicant): The goal of this proposal is to elucidate the role of IgA and gastrointestinal lymphoid tissues (GALT) in Clostridium difficile (CD) immunity. CD is a gastrointestinal pathogen that is a major and increasing health care burden costing the United States an estimated 3 billion dollars/year and an estimated 7,752-20,000 deaths occurring annually from CD infection and disease (CDI). Risk factors for acquiring CDI include antibiotic therapy, age (>65 years), hospitalization, and failure to mount or maintain an adequate antibody response to the CD toxins. The need for safe and effective vaccines that induce neutralizing antibody to the CD toxins and reduce CDI burden is paramount. The CD toxins are produced in the colon where gastrointestinal lymphoid tissues (GALT) predominantly produce IgA, which is the major defense mechanism of the gut from pathogens and toxins. Antigen-specific IgG responses are also induced in the GALT that may contribute to serum IgG pools. No studies have identified whether IgA or GALT is required for CDI protection. The majority of candidate CD vaccines are parenteral vaccines that induce CD toxin-specific serum IgG but do not induce intestinal IgA, which may be required to obtain robust protection against CDI. Non-CD parenteral vaccines adjuvanted with the vitamin A metabolite all trans retinoic acid (RA) induce gut targeted homing of IgA antibody secreting cells and production of antigen-specific IgA. The objective of this application is to define protective immunological pathways that are induced during CDI. We hypothesize that the GALT and IgA are critical for protective immunity to CDI and that inclusion of RA with parenterally administered CD vaccines will significantly enhance protective immunity through the enhancement of mucosal IgA. This hypothesis will be addressed by answering the following questions. Aim 1: Determine whether IgA is critical to CDI protective immunity. Is IgA required for protection against CDI infection? Does RA induce colonic toxin-specific IgA and enhance CDI protective immunity? Aim 2: Determine whether colonic immune responses are important in protective immunity to CDI. Are both IgA and IgG antibody responses to CD toxins initiated in GALT? Does the absence of GALT ablate protection from CDI? The proposed studies are innovative as they challenge key facets of the prevailing model of protective immunity to CDI and at their conclusion, we will have defined for the first time the role of mucosal IgA and GALT in protective immunity to CDI and identified new approaches to enhance protection induced by parenteral vaccines through induction of intestinal IgA by adjuvants like RA. Our proposed studies promise to yield novel and important insights to CD immunity relevant to CDI therapy and targeted vaccine design.

描述（由申请方提供）：本提案的目的是阐明伊加和胃肠道淋巴组织（GALT）在艰难梭菌（CD）免疫中的作用。CD是一种胃肠道病原体，是一种主要的且不断增加的卫生保健负担，估计每年花费美国30亿美元，并且估计每年有7，752 - 20，000人死于CD感染和疾病（CDI）。获得CDI的风险因素包括抗生素治疗、年龄（>65岁）、住院治疗以及未能对CD毒素产生或维持足够的抗体应答。对诱导CD毒素中和抗体并减少CDI负担的安全有效疫苗的需求至关重要。CD毒素在结肠中产生，其中胃肠道淋巴组织（GALT）主要产生伊加，IgA是肠道抵抗病原体和毒素的主要防御机制。在GALT中也诱导抗原特异性IgG应答，这可能有助于血清IgG池。没有研究确定CDI保护是否需要伊加或GALT。大多数候选CD疫苗是诱导CD毒素特异性血清IgG但不诱导肠道伊加的胃肠外疫苗，这可能是获得针对CDI的稳健保护所需的。用维生素A代谢物全反式视黄酸（RA）作为佐剂的非CD肠胃外疫苗诱导伊加抗体分泌细胞的肠道靶向归巢和抗原特异性伊加的产生。本申请的目的是确定在CDI期间诱导的保护性免疫途径。我们假设GALT和伊加对于CDI的保护性免疫是至关重要的，并且将RA与胃肠外施用的CD疫苗包括在内将通过增强粘膜伊加来显著增强保护性免疫。这个假设将通过回答以下问题来解决。目的1：确定伊加是否对CDI保护性免疫至关重要。 伊加是预防CDI感染所必需的吗？ RA是否诱导结肠毒素特异性伊加并增强CDI保护性免疫？目的2：确定结肠免疫应答在CDI保护性免疫中是否重要。 对CD毒素的伊加和IgG抗体反应是否都在GALT中启动？ GALT的缺失是否会对CDI产生消融保护？所提出的研究是创新的，因为它们挑战了CDI保护性免疫的流行模型的关键方面，并且在其结论中，我们将首次定义粘膜伊加和GALT在CDI保护性免疫中的作用，并确定了通过佐剂如RA诱导肠道IgA来增强胃肠外疫苗诱导的保护的新方法。我们提出的研究有望产生新的和重要的见解CD免疫相关的CDI治疗和靶向疫苗设计。