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

基本信息

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
项目类别：
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

项目摘要

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。迄今为止，我们无法准确预测哪些人未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并面临不适当的风险。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此类免疫反应必须成为预防目标。我们的长期目标是确定细胞免疫表型，该表型使个体在口腔感染牙周病原体后容易破坏牙齿周围的结缔组织和骨骼。我们当前的目标是研究对牙龈卟啉单胞菌敏感 (BALB/c) 或耐药 (C57BL/6) 的小鼠品系中两种牙龈卟啉单胞菌 (RgpA 和 Kgp) 特异性的 CD4+ 效应 T 细胞的激活动力学和表型 -介导牙周骨破坏。我们假设，在遗传易感疾病的小鼠中，RgpA 和 Kgp 特异性 CD4+ T 辅助 (Th) 细胞分化为骨破坏性 IFN-α 细胞。产生 Th1 细胞，并在牙周骨破坏开始后转变为 Th17 表型。为了检验这一假设，我们将使用一种新型抗原特异性四聚体染色，首先确定 R/Kgp 特异性效应细胞和调节性 CD4+ T 细胞的激活动力学和表型，以及牙龈卟啉单胞菌定植的牙槽骨破坏的相对量BALB/c 和 C57BL/6 小鼠。同时，我们将定义边缘牙龈中炎症细胞浸润的性质和时间。其次，我们将通过一系列过继转移实验来确定 R/Kgp 特异性效应 Th 细胞对骨水平的直接影响。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种小鼠品系的骨破坏或保护的动力学。此外，这些结果将支持随后的 R01 应用，测试细胞因子和 RANKL（具体由 R/Kgp 特异性 CD4+ T 细胞或同种型转换 B 细胞产生）对牙槽骨稳态的影响以及边缘牙龈内先天免疫的作用在对牙周骨破坏敏感或抵抗的小鼠品系中。建立预测未来牙周骨破坏的框架对于了解牙周病进展的发病机制、定制牙周治疗以及最终开发针对牙周炎的粘膜疫苗至关重要。