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）： 越来越需要新的和更好的疫苗来对抗传染病和恶性疾病。 这种需求反映了抗生素耐药性微生物和新的传染性病原体以及潜在的生物恐怖生物体数量的增加。目前许多恶性肿瘤的治疗依赖于非特异性和高毒性的药物，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有效的治疗，更好地保护患者的健康和生活质量的承诺随着退伍军人人口的老龄化，有癌症的发病率增加，以及自身免疫和炎症条件。我们的中心假设是，了解免疫反应如何通过多种信号的相互作用来调节是开发有效免疫疗法（包括疫苗）的关键。这种相互作用的最重要的集合之一是激活先天免疫的信号和调节抗原特异性适应性免疫应答的信号之间的相互作用。了解这些相互作用对于理解免疫反应如何工作以及有效地操纵免疫反应至关重要。这个基本的免疫学建议的重点是获得一个更完整的了解微生物核酸受体如何与其他免疫受体在B淋巴细胞的活化，与应用这些知识，以更好的疫苗开发策略的长期目标。 在目前的项目期间，我们获得了重要的机制的见解之间的相互作用的先天性和适应性免疫受体在B淋巴细胞。这些见解被应用于通过先天免疫系统的toll样受体（TLR）调节对信号的响应性，以及使用B细胞作为细胞疫苗。下一个项目期的工作建议建立在这些发现的基础上，以获得额外的机制见解和优化B细胞疫苗的有效性。我们将追求两个主要的实验目的：1）使用对感染性病原体的模型应答和肿瘤模型来优化B细胞疫苗中先天性和适应性免疫受体相互作用的相互作用，和2）检查在B细胞活化、先天性免疫耐受和B细胞疫苗接种中经由B细胞抗原受体、toll样受体和干扰素受体递送的信号之间的相互作用。