Treatment of Periodontitis via Recruitment of Regulatory Lymphocytes

描述（由申请人提供）：越来越清楚的是，牙周炎不仅以致病性感染为特征，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，我们实验室最近的数据表明，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失。我们假设treg招募因子的控释制剂是再生牙周间隙的可行方法。我们的初步数据表明，Treg募集因子的控制释放导致牙周组织和引流淋巴结中调节性t细胞的增加，从而缓解牙周病症状，这一假设得到了支持。具体目标一：设计能影响牙周组织中Tregs数量和消除牙周炎症状的控释制剂。我们将合理设计和制备控释微颗粒，产生不同的Treg募集因子释放谱，并利用两种不同的牙周病小鼠模型研究其对牙槽骨丢失的影响。此外，我们将通过控制几种关键分子的组合释放，探索局部淋巴细胞向丰富Tregs群体的扩展。专项目的二：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，以及缺乏Treg迁移和功能重要受体的小鼠的趋化性，来研究Treg在牙周组织中的趋化机制。然后，我们将在单次注射我们的初步CCL22微粒制剂后，研究炎症条件下Treg在牙周组织中的停留时间。我们还将研究与treg和组织代谢相关的分子标记的表达水平，以阐明treg介导的牙周病消除的机制。

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.