Treatment of periodontitis by homing M2 macrophages

归巢M2巨噬细胞治疗牙周炎

• 批准号: 9296130
• 负责人: CHARLES SFEIR
• 金额: $ 23.05万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9296130
• 关键词: Address; Adult; Affect; Alveolar Bone Loss; Anti-Inflammatory Agents; Anti-inflammatory; Bacteria; Bacterial Infections; Behavior; Biological; Biological Assay; Birth; CCL17 gene; CCL2 gene; CCL22 gene; Calculi; Canis familiaris; Cardiovascular Diseases; Cells; Chemotaxis; Chronic; Clinical Treatment; Control Groups; Data; Debridement; Dental Calculus; Dental Plaque; Dental caries; Diabetes Mellitus; Disease; Disease model; Enzyme-Linked Immunosorbent Assay; Gingival Pocket; Glycolates; Homing; Immune; Immune response; Immunohistochemistry; Impaired wound healing; In Vitro; Inbred BALB C Mice; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Injectable; Interleukin-10; Interleukin-13; Interleukin-4; Intestines; Laboratories; Lymphocyte; Methods; Microbe; Modeling; Morphology; Mouth Diseases; Mus; Outcome Study; Periodontal Diseases; Periodontal Pocket; Periodontitis; Phenotype; Play; Population; Property; Public Health; Recombinants; Recruitment Activity; Regulatory T-Lymphocyte; Research; Resolution; Role; Root Scaling; Signal Recognition Particle; Site; Systemic disease; Techniques; Technology; Testing; Therapeutic; Tissues; Tooth Loss; Topical Antibiotic; Transforming Growth Factor beta; Translating; United States; X-Ray Computed Tomography; aged; alveolar bone; bone loss; chemokine; cytokine; immunoregulation; in vivo; macrophage; monocyte; mouse model; new therapeutic target; pathogen; response; standard care; tooth surface; treatment strategy

PROJECT SUMMARY Periodontitis is the second most common oral disease, affecting about half of adults (65 millions) in the United States. Periodontitis causes tooth loss and has been implicated in several serious systemic diseases include diabetes, cardiovascular diseases, and immature birth. Periodontitis is a chronic inflammatory disease, triggered by bacterial infection present in dental plaques and calculus, but the disease itself is caused by host immune response to these pathogens. Current standard treatment is debridement of plaques and calculus to reduce the bacterial load, however, there are no therapies to address the immune aspect of the diseases. Thus, many research groups have started developing technologies to regulate the immune response and reduce inflammation. Our group has focused so far on recruiting T regulatory immune cells new target for therapy of periodontitis. In the previous study, we have successfully reduced alveolar bone loss by recruiting regulatory T cells in mouse and dog periodontitis model. Regulatory T cells were recruited by injecting C-C motif chemokine 22 (CCL22) releasing PLGA microparticles in the periodontal pockets. These results indicated that recruiting regulatory immune cells by local delivery of chemokine indeed reduces inflammation and bone loss in periodontitis. To further explore the principle of “recruitment of regulatory immune cells” and to continue our efforts to develop better therapies, we hypothesize that recruiting a larger population of anti-inflammatory immune cells such as M2 macrophages will achieve a better therapeutic option. Macrophages plays an important role in inflammatory responses, and interestingly have a polarization property by differentiating into M1 (pro- inflammatory) or M2 (anti-inflammatory) macrophages. Our hypothesis that is strongly supported by our recent in vivo pilot data is that the local delivery of CCL2 will induce homing of M2 macrophages, and differentiation of macrophages and monocytes to an M2 phenotype leading to decreased inflammation and bone loss in periodontal tissue. To test this hypothesis, we set the following specific aims; 1) To fabricate CCL2 releasing microparticles and analyze recruitment of M2 macrophage and differentiation of macrophages and monocytes to M2 macrophages and 2) To analyze effect of CCL2 on periodontitis in mouse model. We anticipate that CCL2 released from PLGA microparticles will recruit and induce M2 macrophages, and reduce inflammation and bone loss of periodontal tissue in mouse periodontitis model. Moreover, this concept could be applied to therapies for other inflammatory diseases such as delayed wound healing of diabetes or bowel disease.

项目概要 牙周炎是第二大常见口腔疾病，影响美国约一半成年人（6500 万人） 国家。牙周炎会导致牙齿脱落，并与多种严重的全身性疾病有关，包括 糖尿病、心血管疾病和早产。牙周炎是一种慢性炎症性疾病， 由牙菌斑和牙石中存在的细菌感染引发，但疾病本身是由宿主引起的 对这些病原体的免疫反应。目前的标准治疗是清除斑块和牙石 减少细菌负荷，但是，没有治疗方法可以解决疾病的免疫方面问题。 因此，许多研究小组已经开始开发调节免疫反应和 减少炎症。迄今为止，我们的团队专注于招募 T 调节性免疫细胞作为新靶点 牙周炎的治疗。 在之前的研究中，我们通过在体内招募调节性T细胞，成功减少了牙槽骨丢失。 小鼠和狗牙周炎模型。通过注射 C-C 基序趋化因子 22 来招募调节性 T 细胞 (CCL22) 在牙周袋中释放 PLGA 微粒。这些结果表明，招募 通过局部递送趋化因子的调节性免疫细胞确实可以减少炎症和骨质流失 牙周炎。 进一步探索“招募调节性免疫细胞”的原理，继续努力 为了开发更好的疗法，我们假设招募更多的抗炎免疫细胞 例如M2巨噬细胞将实现更好的治疗选择。巨噬细胞在以下方面发挥重要作用 炎症反应，有趣的是通过分化为 M1（亲 炎症）或 M2（抗炎）巨噬细胞。我们的假设得到了我们最近的大力支持 体内试验数据是 CCL2 的局部递送将诱导 M2 巨噬细胞归巢，并且 巨噬细胞和单核细胞分化为 M2 表型，从而减少炎症 和牙周组织骨质流失。为了检验这一假设，我们设定了以下具体目标； 1) 至 制造 CCL2 释放微粒并分析 M2 巨噬细胞的募集和分化 巨噬细胞和单核细胞到 M2 巨噬细胞以及 2) 分析 CCL2 对小鼠牙周炎的影响 模型。 我们预计从 PLGA 微粒释放的 CCL2 将招募并诱导 M2 巨噬细胞，并且 减少小鼠牙周炎模型中牙周组织的炎症和骨丢失。而且，这个概念 可应用于其他炎症性疾病的治疗，例如糖尿病伤口愈合延迟或 肠道疾病。