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，影响美国人群的30-40％。它是牙周组织破坏和牙齿脱落的主要原因。迄今为止，我们无法准确预测哪些人将发展未来的牙周骨骼破坏，导致大多数牙科患者接受不必要的治疗和暴露于不当风险。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可能以肺泡骨破坏结束。在发生骨骼损伤之前抑制这种免疫反应必须成为预防的目标。我们的远距离目标是定义细胞免疫表型，该表型使人有可能破坏与牙周病原体口腔感染后牙齿周围的结缔组织和骨骼。我们目前的目的是研究针对小鼠菌株（BALB/C）或抗性（C57BL/6）对P. gingivalis介导的周期性元素二期元素骨骼销毁的小鼠菌株（BALB/C）或抗性（BALB/C）或抗性（BALB/C）或抗性（BALB/C/6）中CD4+效应T细胞（RGPA和KGP）特异的激活和表型的动力学。我们假设在遗传上易受疾病的小鼠中，RGPA和KGP特异性CD4+ T助手（Th）细胞分化为破坏性的IFN-？已经开始产生Th1细胞，并在牙周骨破坏后进入Th17表型。为了检验这一假设，我们将使用新型的抗原特异性四聚体染色来首先确定R/KGP特异性效应子的激活和表型的动力学和调节性CD4+ T细胞，以及牙齿牙周疟原虫骨骼破坏的相对量。同时，我们将定义边缘牙龈中炎症细胞浸润的性质和时机。其次，我们将使用一系列收养转移实验确定R/kGP特异性效应子TH细胞对骨骼水平的直接影响。总的来说，这些数据将定义哪种R/KGP特异性TH细胞的表型将驱动每种小鼠菌株中骨骼破坏或保护的动力学。此外，这些结果将支持随后的R01申请测试，以测试细胞因子和RANKL的影响，这是由R/KGP特异性的CD4+ T细胞或同种型交换B细胞对肺泡骨稳态的作用，以及Margical Gingiva在Marginal Gingiva中的作用，在小鼠菌株中均具有抗骨状的骨骼。建立一个预测未来牙周骨破坏的框架对于了解牙周疾病进展，定制牙周治疗以及最终开发针对牙周炎的粘膜疫苗的发病机理至关重要。