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: 8423814
• 负责人: Prosper N Boyaka
• 金额: $ 34.55万
• 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 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8423814
• 关键词: Abbreviations; Address; Adenylate Cyclase; Adjuvant; Adverse effects; Animal Model; Anthrax disease; Antibodies; Antigen-Presenting Cells; Antigens; Apoptosis; B-Lymphocytes; 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 cell response; 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; receptor; respiratory; response; scorpion toxin I' ' ; seasonal influenza; stem; trafficking; training aid; vaccine delivery

Abstract 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.

抽象的 鼻咽道是使人衰弱和可能致命的病原体的主要入口 包括炭疽杆菌和流感病毒。粘膜疫苗能够促进抗体和 除一般血液外，粘膜组织中的细胞毒性 T 细胞反应还可以保护更多 比传统的注射疫苗更有效地抵抗呼吸道病原体。因此，需要 用于安全的粘膜佐剂和疫苗输送系统。这笔赠款之前的工作重点是 将小鼠鼻相关淋巴网状组织（NALT）定义为免疫诱导位点 针对鼻咽道的反应。我们使用霍乱毒素并开发了新型衍生物 缺乏 ADP 核糖基转移酶活性，无法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 包括特别强调炭疽保护性抗原抗体 (Abs) 的表征 保护粘膜组织的潜力。总共五个原始具体目标已成功实现 已解决。在我们的研究过程中，一个重大且意想不到的发现是鼻腔 炭疽芽孢杆菌保护性抗原与 cAMP 诱导突变体共同施用 炭疽杆菌水肿因子增强了针对这两种物质的粘膜和全身免疫力 分子。此外，我们发现水肿毒素（EdTx 或保护性抗原加上水肿 因子）衍生物增强对共同施用的无关抗原的粘膜和全身免疫力 例如重组鼠疫耶尔森氏菌F1-V抗原。与神经节苷脂结合肠毒素霍乱不同 毒素，EdTx 或其衍生物在鼻腔施用后均不靶向中枢神经系统组织。在 这笔续签拨款，我们将解决 EdTx 舌下应用的总体假设 衍生物将诱导基于 NALT 的免疫力并预防呼吸道病原体，而无需 不良反应通常与鼻腔施用肠毒素有关。将制定具体目标 水肿因子衍生物与保护性抗原（PA）共同施用的佐剂活性 舌下途径增强对炭疽毒素成分的免疫力。具体目标二 表征舌下免疫对呼吸道病毒感染的保护性免疫力 EdTx 衍生物作为佐剂。具体目标三的研究将确定 舌下免疫后分泌型 IgA (SIgA) Ab 的产生和粘膜免疫 EdTx 衍生物。最后，具体目标四将确定诱导的分子信号 EdTx 衍生物作为舌下佐剂的 SIgA 反应。这笔赠款将阐明机制 EdTx 衍生物可作为舌下疫苗的佐剂并诱导基于 NALT 的免疫。 我们还将验证一种新的粘膜疫苗递送途径，以及新的基于 PA 的粘膜疫苗 用于诱导针对呼吸道病原体的免疫力的佐剂。

项目成果

Th1 and Th2 cells are required for both eosinophil- and neutrophil-associated airway inflammatory responses in mice.

Th1 和 Th2 细胞是小鼠嗜酸性粒细胞和中性粒细胞相关气道炎症反应所必需的。

• 发表时间: 2007-05-25
• 影响因子: 3.1
• 作者: Fischer, Romy;Tomé, Daniel;McGhee, Jerry R;Boyaka, Prosper N
• 通讯作者: Boyaka, Prosper N

Neutrophils negatively regulate induction of mucosal IgA responses after sublingual immunization.

舌下免疫后中性粒细胞负向调节粘膜 IgA 反应的诱导。

• 发表时间: 2015-07
• 影响因子: 8
• 作者: Jee, J;Bonnegarde;Duverger, A;Iwakura, Y;Cormet;Martin, T L;Steiner, H E;Bachman, R C;Boyaka, P N
• 通讯作者: Boyaka, P N

Cutting edge: the mucosal adjuvant cholera toxin redirects vaccine proteins into olfactory tissues.

最前沿：粘膜佐剂霍乱毒素将疫苗蛋白重新定向到嗅觉组织中。

• 发表时间: 2000-11-01
• 作者: van Ginkel, F W;Jackson, R J;Yuki, Y;McGhee, J R
• 通讯作者: McGhee, J R

Routes of allergic sensitization and myeloid cell IKKβ differentially regulate antibody responses and allergic airway inflammation in male and female mice.

过敏致敏途径和骨髓细胞 IKKβ 差异调节雄性和雌性小鼠的抗体反应和过敏性气道炎症。

• 发表时间: 2014
• 影响因子: 3.7
• 作者: Bonnegarde;Jee, Junbae;Fial, Michael J;Steiner, Haley;DiBartola, Stephanie;Davis, Ian C;Cormet;Tomé, Daniel;Boyaka, Prosper N
• 通讯作者: Boyaka, Prosper N

Inducing Mucosal IgA: A Challenge for Vaccine Adjuvants and Delivery Systems.

诱导粘膜 IgA：疫苗佐剂和递送系统的挑战。

• 发表时间: 2017-07-01
• 作者: Boyaka; Prosper N
• 通讯作者: Prosper N