Alternative approaches for NALT-based immunity to respiratory pathogens

基于 NALT 的呼吸道病原体免疫替代方法

• 批准号: 7585079
• 负责人: Prosper N Boyaka
• 金额: $ 37.5万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-03-15 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7585079
• 关键词: Abbreviations; Address; Adenylate Cyclase; Adjuvant; Adverse effects; Animal Model; Anthrax disease; Antibodies; Antigen-Presenting Cells; Antigens; Apoptosis; Bacillus anthracis; Binding; Blood Circulation; Bronchoalveolar Lavage; Cholera Toxin; Cyclic AMP; Cytotoxic T-Lymphocytes; Delayed Hypersensitivity; Dendritic Cells; Development; Diarrhea; Dose; Edema; Effectiveness; Enterotoxins; Epithelial Cells; Epithelium; Escherichia coli; Event; Fluids and Secretions; Gangliosides; Gastrointestinal tract structure; Generations; Grant; Heating; Histocompatibility Antigens Class II; Homing; Human; Immune; Immune response; Immunity; Immunization; Immunoglobulin A; Inflammatory Response; Ingestion; Intestines; Lung; MHC Class II Genes; Medical; Mesentery; Molecular; Mucosal Immunity; Mucous Membrane; Mus; Myelogenous; Neuraxis; Nose; Olfactory Nerve; Oral; Pathway interactions; Phenotype; Polymeric Immunoglobulin Receptors; Receptor Signaling; Recombinants; Recruitment Activity; Reporter; Role; Route; Secretory Immunoglobulin A; Signal Transduction; Site; Structure of aggregated lymphoid follicle of small intestine; System; T-Lymphocyte; Testing; Tissues; Toll-like receptors; Toxin; Transferase; Transgenic Mice; Urinary tract; Vaccination; Vaccine Antigen; Vaccines; Viral; Virulence; Virus Diseases; Work; Yersinia pestis; Yersinia pestis caf1 protein; abstracting; anthrax edema factor; anthrax lethal factor; anthrax protective factor; anthrax toxin; anthrax toxin receptors; base; edema factor; ganglioside receptor; gastrointestinal; influenza epidemic; influenza virus vaccine; influenzavirus; lymph nodes; macrophage; mucosal vaccine; mutant; novel; novel vaccines; pathogen; public health relevance; receptor; respiratory; response; scorpion toxin I' ' ; seasonal influenza; stem; trafficking; training aid; vaccine delivery

DESCRIPTION (provided by applicant): The nasopharyngeal tract is a major portal entry of debilitating and potentially lethal pathogens including Bacillus anthracis and influenza virus. Mucosal vaccines capable of promoting antibody and cytotoxic T cell responses in mucosal tissues, in addition to the general bloodstream, protect more effectively against respiratory pathogens than classical injected vaccines. Therefore, there is a need for safe mucosal adjuvants and vaccine delivery systems. Previous work on this grant focused at defining murine nasal-associated lymphoreticular tissues (NALT) as inductive sites for immune responses targeting the nasopharyngeal tract. We used cholera toxin and developed novel derivatives lacking ADP ribosyl transferase activity to circumvent the reactogenicity of this enterotoxin adjuvant. In addition, we have assessed the action of anthrax toxins on murine NALT. These studies have also included the characterization of antibodies (Abs) to anthrax protective antigens with special emphasis on the potential to protect mucosal tissues. A total of five original Specific Aims were successfully addressed. A major and unexpected finding during the course of our studies was the fact the nasal co-administration of Bacillus anthracis protective antigen together with a mutant of the cAMP-inducing Bacillus anthracis edema factor enhanced mucosal and systemic immunity against these two molecules. Furthermore, we found that the edema toxin (EdTx or protective antigen plus edema factor) derivative enhanced mucosal and systemic immunity to co-administered unrelated antigens such as recombinant Yersinia pestis F1-V antigen. Unlike the ganglioside-binding enterotoxin cholera toxin, neither EdTx nor its derivatives target central nervous system tissues after nasal application. In this renewal grant, we will address the overall hypothesis that sublingual application of EdTx derivatives will induce NALT-based immunity and protect against respiratory pathogens, without the adverse effects often associated with nasal application of enterotoxins. Specific aim one will establish the adjuvant activity of edema factor derivatives co-administered with protective antigen (PA) via the sublingual route for enhanced immunity to anthrax toxin components. Specific aim two will characterize protective immunity to respiratory viral infection afforded by sublingual immunization with EdTx derivatives as adjuvant. Studies in specific aim three will identify inductive sites for the generation of secretory IgA (SIgA) Abs and mucosal immunity after sublingual immunization with EdTx-derivatives. Finally, specific aim four will determine molecular signals underlying the induction of SIgA responses by EdTx-derivatives as sublingual adjuvant. This grant will unravel the mechanisms by which EdTx derivatives act as adjuvant for sublingual vaccines and induce NALT-based immunity. We will also validate a new route for mucosal vaccine delivery, as well as new PA-based mucosal adjuvant(s) for the induction of immunity against respiratory pathogens. PUBLIC HEALTH RELEVANCE: Thus far, nasal delivery of vaccines was believed to be the most effective mean to trigger inductive sites of immune responses for the development of optimal immunity against respiratory pathogens. However, enterotoxin adjuvants employed in nasal vaccines could induce severe side effects resulting from their ability to target the central nervous system and sustain inflammatory responses. This grant will explore the efficacy of edema toxin derivatives as adjuvant for sublingual vaccines. Upon completion, we will have validated a new vaccine delivery system, as well as new mucosal adjuvant(s) for the induction of immunity against respiratory pathogens.

描述（由申请人提供）：鼻咽道是使人衰弱和可能致命的病原体（包括炭疽杆菌和流感病毒）的主要入口入口。除一般血液外，粘膜疫苗还能够促进粘膜组织中的抗体和细胞毒性 T 细胞反应，比传统的注射疫苗更有效地预防呼吸道病原体。因此，需要安全的粘膜佐剂和疫苗递送系统。该资助项目之前的工作重点是将小鼠鼻相关淋巴网状组织（NALT）定义为针对鼻咽道的免疫反应的诱导位点。我们使用霍乱毒素并开发了缺乏 ADP 核糖基转移酶活性的新型衍生物，以规避这种肠毒素佐剂的反应原性。此外，我们还评估了炭疽毒素对小鼠 NALT 的作用。这些研究还包括炭疽保护性抗原抗体 (Abs) 的表征，特别强调保护粘膜组织的潜力。总共五个最初的具体目标已成功实现。我们研究过程中的一个重大且意想不到的发现是，鼻腔共同施用炭疽杆菌保护性抗原和 cAMP 诱导炭疽杆菌水肿因子的突变体增强了针对这两种分子的粘膜和全身免疫力。此外，我们发现水肿毒素（EdTx 或保护性抗原加水肿因子）衍生物增强了对共同施用的无关抗原（例如重组鼠疫耶尔森菌 F1-V 抗原）的粘膜和全身免疫力。与神经节苷脂结合肠毒素霍乱毒素不同，EdTx 及其衍生物在鼻腔施用后均不会靶向中枢神经系统组织。在这笔续展资助中，我们将提出一个总体假设，即舌下应用 EdTx 衍生物将诱导基于 NALT 的免疫力并预防呼吸道病原体，而不会产生与鼻腔应用肠毒素相关的不良反应。具体目标一是确定水肿因子衍生物与保护性抗原（PA）通过舌下途径共同施用的佐剂活性，以增强对炭疽毒素成分的免疫力。具体目标二将表征以 EdTx 衍生物作为佐剂的舌下免疫所提供的对呼吸道病毒感染的保护性免疫力。具体目标三的研究将确定使用 EdTx 衍生物舌下免疫后产生分泌型 IgA (SIgA) Ab 和粘膜免疫的诱导位点。最后，具体目标四将确定 EdTx 衍生物作为舌下佐剂诱导 SIgA 反应的分子信号。这笔资助将揭示 EdTx 衍生物作为舌下疫苗佐剂并诱导基于 NALT 的免疫的机制。我们还将验证一种新的粘膜疫苗递送途径，以及用于诱导针对呼吸道病原体的免疫力的新型 PA 粘膜佐剂。公共卫生相关性：迄今为止，鼻腔注射疫苗被认为是触发免疫反应诱导位点以形成针对呼吸道病原体的最佳免疫力的最有效方法。然而，鼻疫苗中使用的肠毒素佐剂可能会引起严重的副作用，因为它们能够靶向中枢神经系统并维持炎症反应。这笔赠款将探索水肿毒素衍生物作为舌下疫苗佐剂的功效。完成后，我们将验证一种新的疫苗输送系统以及用于诱导针对呼吸道病原体的免疫力的新粘膜佐剂。