Understanding and applying innate and adaptive immune signal interactions

描述(由申请人提供)： 人们越来越需要新的和更好的疫苗，以对抗传染病和恶性疾病。这一需求反映了抗药性微生物、新的感染性病原体以及潜在的生物恐怖生物数量的增加。目前许多治疗恶性肿瘤的药物依赖于非特异性和剧毒的药物，这些药物会对正常器官和组织以及恶性细胞造成严重损害。抗肿瘤疫苗有望提供更具体和有效的治疗，更好地保护患者的健康和生活质量。随着退伍军人人口的老龄化，癌症发病率以及自身免疫和炎症状况的增加。我们的中心假设是，了解免疫反应是如何受到多种信号相互作用调节的，是开发包括疫苗在内的有效免疫疗法的关键。这类相互作用中最重要的一组是激活天然免疫的信号和调节抗原特异性适应性免疫反应的信号之间的相互作用。了解这些相互作用对于了解免疫反应如何工作以及有效操纵免疫反应都是至关重要的。这一基本免疫学建议的重点是更全面地了解微生物核酸受体在B淋巴细胞激活过程中如何与额外的免疫受体相互作用，长期目标是将这种知识应用于疫苗开发的更好策略。在目前的项目期间，我们对B淋巴细胞中天然免疫受体和获得性免疫受体之间的相互作用获得了重要的机制见解。这些见解被应用于通过先天免疫系统的Toll样受体(TLR)调节对信号的反应性，以及将B细胞用作细胞疫苗。为下一个项目阶段提出的工作建立在这些发现的基础上，以获得更多的机械性见解并优化B细胞疫苗的有效性。我们将追求两个主要的实验目标：1)使用对感染病原体和肿瘤的模型反应，优化B细胞疫苗中先天和获得性免疫受体相互作用的相互作用；2)研究通过B细胞抗原受体、Toll样受体和干扰素受体传递的信号在B细胞激活、先天免疫耐受和B细胞疫苗接种中的相互作用。

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.