Regulation of B Cell Function by Interleukin 12

白细胞介素 12 对 B 细胞功能的调节

• 批准号: 7920519
• 负责人: DENNIS W METZGER
• 金额: $ 40万
• 依托单位: ALBANY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-17 至 2012-09-11
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7920519
• 关键词: Adjuvant; Animals; Antibodies; Antibody Formation; Antigens; B-Cell Activation; B-Lymphocyte Subsets; B-Lymphocytes; Back; Blood Circulation; Cell physiology; Cells; Ensure; Event; Flow Cytometry; Genes; Goals; Human; Humoral Immunities; Hybridomas; Immune Sera; Immune response; Immunity; Immunoglobulin A; Immunoglobulin G; Immunoglobulin-Secreting Cells; Individual; Infection; Infectious Agent; Inflammation; Inflammatory; Interleukin-12; Investigation; Label; Lung; Lymphoid Tissue; Measurement; Mediating; Methods; Microbe; Modeling; Mus; Natural Killer Cells; Polymeric Immunoglobulin Receptors; Process; Production; Receptor Gene; Regulation; Relative (related person); Respiratory System; Respiratory Tract Infections; Respiratory tract structure; Role; Serum; Specificity; Structure; Surface; Testing; Time; Transudate; Vaccination; Vaccine Adjuvant; Vaccines; Viral; Virus Diseases; chemokine; chemokine receptor; cytokine; design; enzyme linked immunospot assay; in vivo; interest; mucosal vaccine; neutralizing monoclonal antibodies; pathogen; receptor expression; research study; respiratory

DESCRIPTION (provided by applicant): The overall objective of this project is to determine the mechanisms required for effective vaccination against respiratory pathogens. Previous experiments have demonstrated that intranasal treatment of mice with vaccine and exogenous IL-12 as adjuvant enhances systemic and mucosal antibody responses, and induces protection against viral and bacterial respiratory infections. Further results have indicated that the observed protection is dependent upon the augmented humoral immune response induced by IL-12. Studies in this proposal are now designed to determine how intranasal IL-12 enhances B cell activity in the lung and to investigate the importance of mucosal versus systemic antibody in pulmonary defense. The hypothesis is that IL-12 stimulates local antibody production, primarily IgA production, and this is responsible for initial defense against infection in the lung. IL-12 may also act synergistically with vaccines/infectious agents to induce a degree of inflammation that allows protective IgG antibody to transudate from the bloodstream and provide a back-up mechanism to ensure survival of the host. To test these concepts, B cell subset activation and recruitment into the lung will be assessed after intranasal vaccination ¿ IL-12. The contributions of T and NK cells, and the cytokines produced by these cells, to enhanced pulmonary B cell activity will be determined using gene deficient animals and antibody depletion/neutralization. The ability of IL-12 to induce localized antibody secreting cells of defined isotype in the lung as well as organized pulmonary lymphoid tissue will be assessed by a combination of ELISPOT and immunohistochemical analyses. Finally, the relative importance of IgA versus IgG for protection against bacterial and viral infection in the lung will be examined using the backpack model with hybridomas of defined antigen specificity and isotype, IgA and polymeric Ig receptor gene deficient mice, and passive transfer of antisera specifically depleted of IgA or IgG. These latter experiments will be performed to examine the potential role of IL-12 in promoting transudation of IgG antibody into the lung. The immediate goal of the study is to determine how a mucosal adjuvant such as IL-12 can enhance lung humoral immunity and protection against infectious microbes. The ultimate goal is to exploit the information obtained in order to understand the requirements for induction of protective pulmonary immunity and to design effective mucosal vaccine adjuvants for use in humans.

描述（由适用提供）：该项目的总体目的是确定有效疫苗针对呼吸道病原体所需的机制。先前的实验表明，用疫苗和外源IL-12对小鼠进行鼻内治疗，作为调整的增强系统性和粘膜抗体反应，并诱导防止病毒和细菌呼吸道感染的保护。进一步的结果表明，观察到的保护取决于IL-12引起的增强体液免疫响应。现在，该提案中的研究旨在确定鼻内IL-12如何增强肺中的B细胞活性，并研究粘膜与全身性抗体在肺防御中的重要性。假设是IL-12刺激局部抗体产生，原代IgA产生，这是造成肺部感染的初始防御。 IL-12还可以与疫苗/感染剂协同作用，以引起一定程度的炎症，从而使受保护的IgG抗体从血液中渗透并提供了确保宿主存活的备用机制。为了测试这些概念，将在鼻内疫苗``IL-12''后评估B细胞子集的激活和募集到肺中。 T和NK细胞的贡献以及这些细胞产生的细胞因子对增强肺B细胞活性的贡献将使用缺乏基因的动物和抗体部署/中和确定。 IL-12在肺中诱导定义同种型的局部抗体分泌细胞以及有组织的肺淋巴组织的能力将通过ELISPOT和免疫组织化学分析的组合进行评估。最后，将使用具有定义的抗原特异性和同型，IgA和聚合物Ig受体缺乏小鼠的杂交型杂交模型来检查IGA与IgG在肺中保护细菌和病毒感染的相对重要性。这些后来的实验将进行检查，以检查IL-12在促进IgG抗体转化为肺中的潜在作用。该研究的直接目标是确定粘膜可调式IL-12等可调如何可以增强肺部体液免疫学和防止感染性微生物的保护。最终目标是利用获得的信息，以了解诱导受保护的肺部免疫学的要求，并设计有效的粘膜疫苗可调型可在人类中使用。