Regulatory B cells in the amelioration of immune-mediated periodontal disease

调节性 B 细胞改善免疫介导的牙周病

• 批准号: 9105732
• 负责人: Xiaozhe Han
• 金额: $ 48.43万
• 依托单位: ADA FORSYTH INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-06 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9105732
• 关键词: Address; Adult; Agonist; Alveolar Bone Loss; American; Animal Model; Antigens; Autoimmune Diseases; Autologous; Award; B-Lymphocytes; Biological; Bone Resorption; CD19 gene; Cell Separation; Cells; Centers for Disease Control and Prevention (U.S.); Clinical Research; Complement 3d Receptors; Data; Dental; Development; Disease; Equilibrium; Expenditure; Future; Gingiva; Goals; Hand; Health; Human; Immune; Immune response; Immune system; Immunoglobulin M; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Institutes; Interleukin-10; Jaw; Knowledge; Laboratories; Life; Ligature; MS4A1 gene; Measurement; Mediating; Methods; Mission; Modality; Molecular; Monoclonal Antibodies; Mononuclear; Mus; Oral; Outcome; PTPRC gene; Pathogenesis; Patients; Periodontal Diseases; Periodontal Infection; Periodontitis; Peripheral Blood Mononuclear Cell; Play; Production; Public Health; Receptor Activation; Regimen; Regulation; Regulatory T-Lymphocyte; Research; Resources; Sampling; Signal Pathway; Site; Specificity; Spleen; Splenocyte; System; T cell differentiation; TLR1 gene; TNFRSF5 gene; TNFSF11 gene; Therapeutic; Tissues; Toll-like receptors; Tooth Loss; Translational Research; Work; aged; base; bone; bone loss; cytokine; disorder prevention; effective therapy; immune function; immunological intervention; immunoregulation; improved; in vivo; in vivo imaging; knowledge translation; migration; mouse model; novel; novel therapeutics; peripheral blood; phenotypic biomarker; prevent

 DESCRIPTION (provided by applicant): Current treatments for periodontitis do not directly address the biological causes of periodontal pathogenesis -- unbalanced, overly aggressive immune responses. Without new strategies to augment current regimens, a substantial number of patients with periodontitis, especially with cases not responsive to current therapies, will continue to suffer the dental and systemic consequences. The long-term goal of our research is to determine immunological strategies that ameliorate periodontal disease in order to promote oral and systemic health. IL- 10-producing regulatory B cells (B10) play a key role in immune system balance, restraining the excessive inflammatory responses by inhibiting pro-inflammatory cytokines and promoting regulatory T cell differentiation. The objective of this application is to determine the mechanism of B10 activation in vitro and B10-mediated abrogation of experimental periodontal bone resorption in vivo. The central hypothesis of this project is that B10 ameliorates periodontal disease bone resorption through antigen-directed gingival migration, and local secretion of IL-10 promotes Treg formation, inhibits Th1 and Th17 activation, and reduces RANKL production. This hypothesis has been formulated on the basis of strong preliminary data produced in the applicants' laboratories supported by a high priority, short-term project award (R56-DE023807). The rationale for the proposed research is that knowledge on how to regulate B10 activity enables novel therapeutic strategies to effectively inhibit the excessive inflammation and bone loss as a local treatment for periodontal disease. The three related specific aims are: 1) To identify the molecular mechanisms for activation and expansion of mouse B10 in vitro. 2) To determine mechanism of B10-mediated abrogation of periodontal inflammation and bone resorption in mouse in vivo. 3) To determine control mechanism of local B10 activation in human gingival mononuclear cells in vitro as first step towards translational research. In vitro B cell isolation/culture system (Aim 1), B cell transfer/ n vivo mouse model of periodontal disease combined with the live cell bioluminescent in vivo imaging approach and quantitative 3-dimentional measurement of periodontal bone loss (Aim 2), and a culture system for in vitro studies using human peripheral blood and gingival tissues obtained from Forsyth Center for Clinical and Translational Research (Aim 3), have all been established as feasible in the applicants' hands. The proposed research is significant because it will enable future development of a novel immunological strategies based on local control of B10 function at the site of periodontal infection and inflammation to treat periodontal disease. The expected outcomes from these aims will be a clear understanding of the mechanisms of B10-meidated abrogation of periodontal bone resorption in vivo in an animal model, and control of B10 function in vitro in local human immune cells from periodontal disease sites.

 描述（由申请人提供）：目前的牙周炎治疗方法不能直接解决牙周发病机制的生物学原因-不平衡，过度积极的免疫反应。如果没有新的策略来加强目前的治疗方案，大量牙周炎患者，特别是对目前治疗无反应的病例，将继续遭受牙齿和全身的后果。我们研究的长期目标是确定改善牙周病的免疫策略，以促进口腔和全身健康。产生IL- 10的调节性B细胞（B10）在免疫系统平衡中起关键作用，通过抑制促炎细胞因子和促进调节性T细胞分化来抑制过度的炎症反应。本申请的目的是确定B10在体外激活和B10介导的实验性牙周骨吸收在体内消除的机制。该项目的中心假设是B10通过抗原导向的牙龈迁移改善牙周病骨吸收，IL-10的局部分泌促进Treg形成，抑制Th 1和Th 17活化，并减少RANKL产生。这一假设是根据申请人实验室产生的强有力的初步数据制定的，这些数据得到了高优先级短期项目奖（R56-DE 023807）的支持。这项研究的基本原理是，关于如何调节B10活性的知识使新的治疗策略能够有效地抑制过度炎症和骨丢失，作为牙周病的局部治疗。本研究的三个主要目的是：1）探讨小鼠B10细胞在体外激活和扩增的分子机制。2)目的：探讨B10抑制小鼠牙周炎和骨吸收的作用机制。3)确定体外人牙龈单个核细胞局部B10激活的控制机制，作为转化研究的第一步。体外B细胞分离/培养系统（目标1），结合活细胞生物发光体内成像方法和牙周骨丢失的定量三维测量的牙周病的B细胞转移/体内小鼠模型（目标2），以及使用从福赛斯临床和转化研究中心获得的人外周血和牙龈组织进行体外研究的培养系统（目标3），在申请人手中都是可行的。这项研究意义重大，因为它将使未来开发一种新的免疫策略，该策略基于牙周感染和炎症部位B10功能的局部控制，以治疗牙周病。这些目标的预期结果将是在动物模型中清楚地了解B10-meidated废除体内牙周骨吸收的机制，以及在牙周病部位的局部人免疫细胞中体外控制B10功能。