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（由申请人提供）：该项目的总体目标是确定针对呼吸道病原体进行有效疫苗接种所需的机制，先前的实验已经证明，用疫苗和外源性 IL-12 作为佐剂对小鼠进行鼻内治疗可增强全身和粘膜抗体反应。进一步的结果表明，观察到的保护作用取决于 IL-12 诱导的增强体液免疫反应。 IL-12 增强肺部 B 细胞活性，并研究粘膜抗体与全身抗体在肺部防御中的重要性。假设是 IL-12 刺激局部抗体产生，主要是 IgA 产生，这负责对感染的初始防御。 IL-12 还可以与疫苗/感染性抗体制剂协同作用，诱导一定程度的炎症，使保护性 IgG 从血液中渗出，并提供后备机制以确保宿主的存活。概念，鼻内疫苗接种后将评估 B 细胞亚群的激活和招募到肺部 ¿ IL-12。T 和 NK 细胞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基因缺陷动物和抗体消耗/中和来确定 IL-12 诱导局部抗体分泌的能力。将通过 ELISPOT 和免疫组织化学分析相结合来评估肺中特定同种型的细胞以及有组织的肺淋巴组织。最后，IgA 与 IgG 在预防细菌和病毒感染方面的相对重要性。将使用具有确定的抗原特异性和同种型的杂交瘤、IgA 和聚合 Ig 受体基因缺陷小鼠的背包模型来检查肺部，并被动转移专门耗尽 IgA 或 IgG 的抗血清，将进行这些后续实验以检查潜在的作用。 IL-12 在促进 IgG 抗体渗出至肺部中的作用 该研究的直接目标是确定粘膜佐剂（如 IL-12）如何增强肺部体液免疫和保护。最终目标是利用所获得的信息来了解诱导保护性肺部免疫的要求并设计用于人类的有效粘膜疫苗佐剂。