P. gingivalis-specific T cells in mice prone and resistant to periodontitis

易患牙周炎和抵抗牙周炎的小鼠体内牙龈卟啉单胞菌特异性 T 细胞

• 批准号: 8507349
• 负责人: MASSIMO COSTALONGA
• 金额: $ 22.8万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8507349
• 关键词: Adoptive Transfer; Affect; Alveolar Bone Loss; Antigens; B-Lymphocytes; Bacteria; C57BL/6 Mouse; CD4 Positive T Lymphocytes; Cells; Cellularity; Characteristics; Chronic; Clonal Expansion; Complex; Connective Tissue; Data; Dental; Disease; Disease Progression; Disorder by Site; Engineering; Epitopes; Exposure to; Flow Cytometry; Funding Mechanisms; Future; Genetic; Gingiva; Goals; Health; Helper-Inducer T-Lymphocyte; Histocompatibility Antigens Class II; Homeostasis; Human; Immune; Immune response; Immune system; Immunoglobulin Class Switching; Inbred BALB C Mice; Individual; Infection; Inflammation; Inflammatory; Interferons; Interleukin-17; Kinetics; Knowledge; Leucocytic infiltrate; Lys-gingipain; Maintenance; Measures; Mediating; Microbial Biofilms; Modeling; Mouse Strains; Mus; Natural Immunity; Nature; Oral; Pathogenesis; Patients; Periodontal Diseases; Periodontitis; Phenotype; Photography; Population; Porphyromonas gingivalis; Predisposition; Prevention; Production; Proliferating; Properdin; Recording of previous events; Regulatory T-Lymphocyte; Relative (related person); Research; Resistance; Risk; Role; Series; Site; Staining method; Stains; System; T memory cell; T-Lymphocyte; TNFSF11 gene; Testing; Th1 Cells; Therapeutic; Time; Tissues; Tooth Loss; Tooth structure; Virulence Factors; Work; alveolar bone; arginyllysine; bone; bone loss; cell population study; congenic; cytokine; digital; experience; gingipain; in vivo; innovation; mouse model; mucosal vaccine; novel; oral infection; pathogen; prevent; public health relevance; research study

DESCRIPTION (provided by applicant): Periodontitis is a chronic inflammatory disease that affects 30-40% of the U.S. population. It is the leading cause of periodontal tissue destruction and tooth loss. To date, we cannot accurately predict which individuals will develop future periodontal bone destruction, leading most dental patients to undergo unnecessary treatment and exposure to undue risk. The periodontal microbiota constantly challenges the immune system, leading, in some cases, to chronic inflammation that may end in alveolar bone destruction. Inhibiting such immune responses before bone damage occurs must become the target of prevention. Our long-range goal is to define the cellular immune phenotype that predisposes an individual to destruction of the connective tissue and bone around teeth subsequent to oral infection with periodontal pathogens. Our current objective is to study the kinetics of activation and phenotype of CD4+ effector T cells specific for two Porphyromonas gingivalis gingipains (RgpA and Kgp) in a mouse strain susceptible (BALB/c) or resistant (C57BL/6) to P. gingivalis-mediated periodontal bone destruction. We hypothesize that in mice genetically susceptible to disease, RgpA- and Kgp-specific CD4+ T helper (Th) cells differentiate into bone destructive IFN-? producing Th1 cells, and into a Th17 phenotype after periodontal bone destruction has been initiated. To test this hypothesis we will use a novel antigen-specific tetramer stain to first, determine the kinetics of activation and phenotype of R/Kgp-specific effector and regulatory CD4+ T cells and the relative amount of alveolar bone destruction in P. gingivalis-colonized BALB/c and C57BL/6 mice. Concurrently, we will define the nature and timing of inflammatory cell infiltrate in the marginal gingiva. Second, we will identify the direct effect of R/Kgp- specific effector Th cells on bone levels using a series of adoptive transfer experiments. Collectively, these data will define which phenotype of R/Kgp-specific Th cells will drive the kinetics of bone destruction or protection in each mouse strain. Furthermore, these results will underpin a subsequent R01 application testing the effect of cytokines and RANKL, specifically produced by R/Kgp-specific CD4+ T cells or isotype-switched B cells, on alveolar bone homeostasis and the role of innate immunity within the marginal gingiva in mouse strains that are susceptible or resistant to periodontal bone destruction. Establishing a framework to predict future periodontal bone destruction is crucial to understanding pathogenesis of periodontal disease progression, customizing periodontal treatment, and ultimately developing a mucosal vaccine against periodontitis.

描述（由申请人提供）：牙周炎是一种慢性炎症性疾病，影响30-40%的美国人口。它是牙周组织破坏和牙齿脱落的主要原因。到目前为止，我们还不能准确预测哪些人将来会发生牙周骨破坏，导致大多数牙科患者接受不必要的治疗和暴露于不必要的风险。牙周微生物群不断挑战免疫系统，在某些情况下导致慢性炎症，最终可能导致牙槽骨破坏。在骨损伤发生之前抑制这种免疫反应必须成为预防的目标。我们的长期目标是确定细胞免疫表型，使个体在口腔感染牙周病原体后易于破坏牙齿周围的结缔组织和骨。我们目前的目的是研究在对牙龈卟啉单胞菌介导的牙周骨破坏敏感（BALB/c）或抗性（C57 BL/6）的小鼠品系中，对两种牙龈卟啉单胞菌牙龈蛋白酶（RgpA和Kgp）特异的CD 4+效应T细胞的活化动力学和表型。我们假设，在小鼠遗传易感疾病，RgpA和Kgp特异性CD 4 + T辅助（Th）细胞分化成骨破坏性IFN-？产生Th 1细胞，并在牙周骨破坏开始后转化为Th 17表型。为了检验这一假设，我们将使用一种新的抗原特异性四聚体染色，首先确定R/Kgp特异性效应和调节性CD 4 + T细胞的活化动力学和表型，以及牙龈卟啉单胞菌定植的BALB/c和C57 BL/6小鼠中牙槽骨破坏的相对量。同时，我们将确定炎症细胞浸润的性质和时间在边缘牙龈。其次，我们将使用一系列过继转移实验来鉴定R/Kgp特异性效应Th细胞对骨水平的直接作用。总的来说，这些数据将定义R/Kgp特异性Th细胞的哪种表型将驱动每个小鼠品系中骨破坏或保护的动力学。此外，这些结果将支持随后的R 01申请，该申请测试了细胞因子和RANKL（由R/Kgp特异性CD 4 + T细胞或同种型转换B细胞特异性产生）对牙槽骨稳态的影响以及对牙周骨破坏敏感或耐药的小鼠品系中边缘牙龈内先天免疫的作用。建立一个框架来预测未来牙周骨破坏是至关重要的了解牙周疾病进展的发病机制，定制牙周治疗，并最终开发一种粘膜疫苗，牙周炎。