Treatment of Periodontitis via Recruitment of Regulatory Lymphocytes

通过招募调节性淋巴细胞治疗牙周炎

• 批准号: 8723640
• 负责人: STEVEN R LITTLE
• 金额: $ 35.4万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8723640
• 关键词: Address; Affect; Alveolar Bone Loss; American; Antibiotics; Antibodies; Biological; Bone Resorption; CCL22 gene; Calculi; Cardiovascular Diseases; Cells; Chemotactic Factors; Chemotaxis; Data; Debridement; Degenerative polyarthritis; Development; Diabetes Mellitus; Disease; Disorder by Site; Drug Formulations; Effectiveness; Engineering; Environment; Future; Gene Expression; Gene Expression Profiling; Glucocorticoids; Glycolates; Growth; Homeostasis; Immune; Immune System Diseases; Immune response; In Situ; In Vitro; Incidence; Infection; Inflammation; Inflammation Mediators; Inflammatory; Injection of therapeutic agent; Kidney Diseases; Laboratories; Lead; Lesion; Ligaments; Lung diseases; Lymphocyte; Lymphocyte Subset; Mediating; Metabolism; Minocycline; Modeling; Monitor; Mus; Natural regeneration; Oral health; Pathology; Patients; Periodontal Diseases; Periodontitis; Periodontium; Physiological; Play; Population; Premature Birth; Process; Proliferating; Proteins; Public Health; Recruitment Activity; Regulation; Regulatory T-Lymphocyte; Resolution; Role; Symptoms; Systemic infection; T-Lymphocyte; Temporomandibular Joint; Testing; Therapeutic; Time; Tissues; Tooth Loss; Treatment Factor; Tumor Necrosis Factor Receptor; Work; bone; chemokine; controlled release; cytokine; design; improved; killings; lymph nodes; migration; molecular marker; mouse model; pathogen; predictive modeling; premature; receptor; residence; response; soft tissue; standard of care

DESCRIPTION (provided by applicant): It is becoming clear that periodontitis is not only characterized by pathogenic infection, but even more so by a loss of immunological homeostasis. Strategies toward resolution of regenerating the periodontium without completely blocking immune responses against local and systemic infections would be ideal. Our long-term objective is to address the physiological cause of periodontitis through an understanding of the inflammatory and regulatory processes of the periodontium. Correspondingly, recent data in our laboratories indicate that periodontitis symptoms are accompanied by the absence of an important cell subset called regulatory T-cells. We hypothesize that controlled release formulations of Treg-recruiting factors is a viable way to regenerate the periodontal space. This hypothesis is supported by our preliminary data demonstrating that controlled release of Treg recruiting factors leads to an increase in regulatory T-cells in the periodontium, in the draining lymph nodes, and, consequently, resolution of periodontal disease symptoms 2 mouse models. Specific Aim I: To engineer controlled release formulations that can influence the number of Tregs in the periodontium and abrogation of the symptoms of periodontitis. We will rationally design and fabricate controlled release microparticles to produce various release profiles of Treg recruiting factors and then examine their effect on alveolar bone loss using two different murine models of periodontal disease. Furthermore, we will explore the expansion of local lymphocytes toward an enriched population of Tregs through controlled release of a combination of several key molecules. Specific Aim II: To better understand the biological mechanisms of Treg recruitment and function in periodontal tissues. We will examine the mechanisms of Treg chemotaxis in the periodontium by monitoring gene expression in response to Treg recruiting therapies and chemotaxis in mice deficient in receptors thought to be important for migration and function of Tregs. We will then investigate the duration of Treg residence in the periodontium under inflammatory conditions after a single injection of our preliminary CCL22 microparticle formulations. We will also examine the expression levels of molecular markers associated with Tregs and tissue metabolism to elucidate the mechanisms of Treg-mediated periodontal disease abrogation.

描述（由申请人提供）：越来越清楚的是，牙周炎不仅以病原体感染为特征，而且更以免疫稳态的丧失为特征。在不完全阻断针对局部和全身感染的免疫反应的情况下，解决牙周组织再生的策略将是理想的。我们的长期目标是通过了解牙周组织的炎症和调节过程来解决牙周炎的生理原因。相应地，我们实验室的最新数据表明，牙周炎症状伴随着一种称为调节性T细胞的重要细胞亚群的缺乏。我们假设，Treg募集因子的控释制剂是再生牙周间隙的可行方法。我们的初步数据支持这一假设，表明Treg募集因子的受控释放导致牙周组织中、引流淋巴结中的调节性T细胞增加，从而缓解牙周病症状2小鼠模型。具体目标一：设计控制释放制剂，可以影响牙周组织中的TdR数量并消除牙周炎症状。我们将合理地设计和制造控释微粒，以产生各种Treg募集因子的释放曲线，然后使用两种不同的牙周病小鼠模型来检查它们对牙槽骨丢失的影响。此外，我们将探索通过控制释放几种关键分子的组合，使局部淋巴细胞向富集的T细胞群扩增。具体目标II：更好地了解牙周组织中Treg募集和功能的生物学机制。我们将通过监测Treg募集疗法的基因表达和受体缺陷小鼠的趋化性来研究牙周组织中Treg趋化性的机制，这些受体被认为对TGFAP的迁移和功能很重要。然后，我们将研究在单次注射我们的初步CCL22微粒制剂后，在炎症条件下Treg在牙周组织中驻留的持续时间。我们还将研究与Treg和组织代谢相关的分子标记物的表达水平，以阐明Treg介导的牙周病消除的机制。