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Mechanisms of Immune Modulation and Periodontal Disease

免疫调节与牙周病的机制

基本信息

批准号：
8089431
负责人：
Jannet Katz
金额：
$ 33.77万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-09-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8089431
关键词：
Affect Antibodies Antigen-Presenting Cells Antigens Bacterial Adhesins Bone Marrow CD80 gene Cardiovascular Diseases Cell physiology Cells Cholesterol Cyclodextrins Cytokine Activation Dendritic Cells Development Disease Effector Cell Esters Event Exposure to Family Fluorescein Fluorescein-5-isothiocyanate Future Glycogen Synthase Kinase 3 Goals Hemagglutinin Histocompatibility Antigens Class II IL2RA gene Immune Immune response Immune system Immunity Immunization Infection Infection prevention Inflammation Inflammatory Intravenous Investigation Isothiocyanates Knock-out Lead Ligands Link Lipopolysaccharides Macrophage Colony-Stimulating Factor Major Histocompatibility Complex Mediating Membrane Microdomains Mitogen-Activated Protein Kinases Molecular Monoclonal Antibodies Natural Immunity Ovalbumin Ovum Pathogenesis Pathologic Pattern Pattern recognition receptor Periodontal Diseases Phycoerythrin Plasma Membrane Lipid Bilayer Play Porphyromonas Porphyromonas gingivalis Process Production Property Regulation Regulatory T-Lymphocyte Role Signal Pathway Signal Transduction Signal Transduction Pathway Signaling Molecule Specificity T cell response T-Cell Activation T-Cell Receptor T-Lymphocyte TNFSF11 gene Testing Toll-like receptors Tumor necrosis factor receptor 11b Up-Regulation Vaccine Therapy Virulence Virulence Factors adaptive immunity base carboxyfluorescein cytokine gingipain immunoregulation innovation insight macrophage microorganism microorganism antigen monocyte novel pathogen receptor research study response subcutaneous therapeutic vaccine therapy development vaccine development

项目摘要

DESCRIPTION (provided by applicant): The innate and adaptive immune systems are irrevocably linked and both play primary roles in the induction and/or prevention of infections, including periodontal disease. Critical to the initiation of innate and adaptive immune responses to microbial antigens is the participation of Toll-like receptors (TLRs), a family of pattern- recognition receptors (PRRs) that detect conserved molecular products of microorganisms. We propose that the immune regulation exerted by the innate immune system upon its interaction with virulence antigens is the basis for the development of therapies geared to manipulate the effector immune response to the advantage and protection of the host. The fundamental hypothesis of our studies is that each microbial antigen is unique in its initial interaction with the host, thus resulting in differences in receptor recognition, activation of signaling pathways and cellular responses. In this regard, we have shown differences in the adaptive immune responses to the hemagglutinin/adhesin virulence antigens Kgp-HArep and HagB derived from Porphyromonas ginigivalis, which suggest that their interactions with the innate immune system differ. We plan to focus our investigations on the TLRs and on dendritic cells since these antigen-presenting cells have the exquisite property of activating na¿ve T cells and thus are critically involved in innate and adaptive responses. In addition, our investigations will pursue an understanding of the ensuing adaptive immune response. Therefore, the aims of this proposal are (1) to determine the role of TLRs in the innate and adaptive response to Kgp-HArep and HagB stimulation; (2) to determine if innate and effector cell responses to Kgp- HArep and HagB require lipid rafts and how the induction of a specific effector response or the use of a certain TLR affects the particular recruitment and concentration of signaling molecules into lipid rafts; and (3) to determine the role of CD25+CD4+ Treg cells in immune responses to Kgp-HArep and HagB and in P. gingivalis infection. It is anticipated that these studies will lead to an understanding of the cellular events that occur when host cells encounter the virulence antigens HArep and HagB, and will provide 1) insight into their role in pathogenesis/immunity and 2) relavant information for the development of vaccines or therapies that will specifically protect or ameliorate infections by the pathogen Porphyromonas gingivalis. Porphyromonas gingivalis is a major etiologic agent of periodontal disease. This inflammatory disease is widespread and associations have been made between this disease and serious systemic conditions such as cardiovascular diseases. Since the immunoregulatory properties of P. gingivalis antigens in host responses are poorly understood, it becomes critical to understand the host cellular responses, including the signaling pathways activated, to major antigens of P. gingivalis, in order to develop novel therapies and vaccines by which periodontal disease can be ameliorated or controlled.

描述（由申请人提供）：先天性免疫系统和适应性免疫系统是不可逆转地联系在一起的，并且两者在诱导和/或预防感染（包括牙周病）中都发挥着主要作用。 Toll 样受体 (TLR) 是启动针对微生物抗原的先天性和适应性免疫反应的关键，TLR 是模式识别受体 (PRR) 家族，可检测微生物的保守分子产物。我们认为，先天免疫系统在与毒力抗原相互作用时所施加的免疫调节是开发旨在操纵效应免疫反应以利于和保护宿主的疗法的基础。我们研究的基本假设是，每种微生物抗原在与宿主的初始相互作用中都是独特的，从而导致受体识别、信号通路激活和细胞反应的差异。在这方面，我们已经表明对源自牙龈卟啉单胞菌的血凝素/粘附素毒力抗原 Kgp-HArep 和 HagB 的适应性免疫反应存在差异，这表明它们与先天免疫系统的相互作用不同。我们计划将研究重点放在 TLR 和树突状细胞上，因为这些抗原呈递细胞具有激活幼稚 T 细胞的优良特性，因此在先天性和适应性反应中发挥着重要作用。此外，我们的研究将寻求对随后的适应性免疫反应的了解。因此，该提案的目的是（1）确定TLRs在对Kgp-HArep和HagB刺激的先天和适应性反应中的作用； (2) 确定对 Kgp-HArep 和 HagB 的先天细胞和效应细胞反应是否需要脂筏，以及特定效应反应的诱导或特定 TLR 的使用如何影响信号分子进入脂筏的特定募集和浓度； (3)确定CD25+CD4+Treg细胞在针对Kgp-HArep和HagB的免疫应答以及牙龈卟啉单胞菌感染中的作用。预计这些研究将有助于了解宿主细胞遇到毒力抗原 HArep 和 HagB 时发生的细胞事件，并将提供 1) 深入了解它们在发病机制/免疫中的作用，以及 2) 开发专门保护或改善病原体牙龈卟啉单胞菌感染的疫苗或疗法的相关信息。牙龈卟啉单胞菌是牙周病的主要病原体。这种炎症性疾病广泛存在，并且已将这种疾病与严重的全身性疾病（例如心血管疾病）联系起来。由于对宿主反应中牙龈卟啉单胞菌抗原的免疫调节特性知之甚少，因此了解宿主细胞对牙龈卟啉单胞菌主要抗原的反应（包括激活的信号通路）变得至关重要，以便开发可改善或控制牙周病的新疗法和疫苗。