Understanding and applying innate and adaptive immune signal interactions

了解和应用先天性和适应性免疫信号相互作用

• 批准号: 8621977
• 负责人: GAIL A. BISHOP
• 金额: --
• 依托单位: IOWA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-10-01 至 2016-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8621977
• 关键词: Activated B-Lymphocyte; Age; Antibiotic Resistance; Antigen-Presenting Cells; Antigens; Autoimmune Process; B-Cell Activation; B-Lymphocytes; Biological Markers; Cancer Model; Cancer Vaccines; Cells; Communicable Diseases; Dendritic Cells; Development; Disease; Effectiveness; Excision; Goals; Health; Human; IFNAR1 gene; Immune; Immune Tolerance; Immune response; Immune system; Immunologic Receptors; Immunology; Immunotherapy; In Vitro; Incidence; Inflammatory; Interferon Receptor; Interferons; Knowledge; Lead; Leukocytes; Malignant - descriptor; Malignant Neoplasms; Microbe; Modeling; Molecular; Mus; Natural Immunity; Nature; Nucleic Acids; Organ; Organism; Patients; Pharmaceutical Preparations; Population; Predisposition; Process; Production; Quality of life; Receptors, Antigen, B-Cell; Regulation; Signal Transduction; Stimulus; T-Lymphocyte; TLR7 gene; Time; Tissues; Toll-like receptors; Vaccination; Vaccine Design; Vaccines; Veterans; Work; cancer cell; clinical practice; combat; design; effective therapy; immune activation; improved; in vivo Model; insight; melanoma; microbial; mortality; neoplastic cell; pathogen; peripheral blood; prevent; public health relevance; receptor; response; tumor; type I interferon receptor; vaccination strategy; vaccine development; vaccine effectiveness

DESCRIPTION (provided by applicant): There is an increasing need for new and better vaccines, to combat both infectious and malignant disease. This need reflects an increased number of antibiotic- resistant microbes, and new infectious pathogens, as well as potential bioterror organisms. Many current treatments of malignancies rely upon nonspecific and highly toxic medications that cause serious damage to normal organs and tissue as well as malignant cells. Anti-tumor vaccines offer the promise of more specific and effective treatments that better preserve the health and life quality of patients As the Veteran population ages, there is increased incidence of cancer, as well as autoimmune and inflammatory conditions. Our central hypothesis is that understanding how immune responses are regulated by the interplay of multiple signals is key to development of effective immunotherapies, including vaccines. One of the most important sets of such interactions is between signals that activate innate immunity and those that regulate the antigen-specific adaptive immune response. Understanding these interactions is crucial both to understand how the immune response works, and to effectively manipulate immune responses. This basic immunology proposal is focused upon gaining a more complete understanding of how receptors for microbial nucleic acids interact with additional immune receptors in the activation of B lymphocytes, with the long-term goal of applying this knowledge to better strategies in vaccine development. During the current project period, we gained important mechanistic insights into interactions between innate and adaptive immune receptors in B lymphocytes. These insights were applied both to the regulation of responsiveness to signals via the toll-like receptors (TLR) of the innate immune system, and use of B cells as cellular vaccines. The work proposed for the next project period builds upon these findings to gain additional mechanistic insights and optimize B cell vaccine effectiveness. We will pursue two major experimental Aims: 1) To optimize the interaction of innate and adaptive immune receptor interactions in B cell vaccines, using both a model response to an infectious pathogen and a tumor model, and 2) To examine the interplay between signals delivered via the B cell antigen receptor, toll-like receptors, and interferon receptors in B cell activation, innate immune tolerance, and B cell vaccination.

描述（由申请人提供）： 越来越需要对新的和更好的疫苗打击感染性和恶性疾病。 这需求反映了抗生素耐药的微生物和新的感染性病原体的数量增加以及潜在的生物疗法。当前的许多恶性肿瘤治疗依赖于非特异性和剧毒药物，这些药物对正常器官和组织以及恶性细胞造成严重损害。 抗肿瘤疫苗提供了更具体和更有效的治疗方法，随着退伍军人人口的年龄，癌症的发生率增加，自身免疫性和炎症状况，可以更好地保留患者的健康和生活质量。我们的核心假设是，了解如何通过多个信号的相互作用来调节免疫反应是开发有效免疫疗法（包括疫苗）的关键。此类相互作用最重要的集合之一是激活先天免疫力的信号与调节抗原特异性适应性免疫反应的信号。了解这些相互作用对于了解免疫反应的工作原理以及有效操纵免疫反应至关重要。该基本的免疫学提案的重点是对微生物核酸的受体在激活B淋巴细胞激活中如何与其他免疫受体相互作用，并具有将这些知识应用于疫苗发育中更好的策略的长期目标。 在当前的项目期间，我们获得了对B淋巴细胞先天和适应性免疫受体之间相互作用的重要机理见解。这些见解既适用于通过固有免疫系统的Toll样受体（TLR）调节对信号的反应性，又将B细胞用作细胞疫苗的使用。下一个项目时期提出的工作基于这些发现，以获得其他机械见解并优化B细胞疫苗的有效性。 We will pursue two major experimental Aims: 1) To optimize the interaction of innate and adaptive immune receptor interactions in B cell vaccines, using both a model response to an infectious pathogen and a tumor model, and 2) To examine the interplay between signals delivered via the B cell antigen receptor, toll-like receptors, and interferon receptors in B cell activation, innate immune tolerance, and B cell vaccination.