Prevention of inflammation-mediated bone loss in murine and canine periodontal disease via recruitment of regulatory lymphocytes
Prevention of inflammation-mediated bone loss in murine and canine periodontal disease via recruitment of regulatory lymphocytes
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DOI：
10.1073/pnas.1302829110
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发表时间：
2013-11-12
影响因子：
11.1
通讯作者：
Little, Steven R.
中科院分区：
文献类型：
--
作者：
Glowacki, Andrew J.;Yoshizawa, Sayuri;Little, Steven R.
牙周病的标志是牙龈软组织和牙槽骨的进行性破坏，这是由炎症引起的，以响应侵入性和持续的细菌侵袭。近年来，它已经变得很明显，这种组织破坏与减少在当地的监管过程，包括减少叉头盒P3表达的调节淋巴细胞。因此，我们开发了一种控释系统，其能够产生用于调节淋巴细胞的已知化学引诱物C-C基序趋化因子配体22（CCL 22）的稳定释放，所述C-C基序趋化因子配体22由具有临床转化的经证实的跟踪记录的可降解聚合物聚（乳酸-共-乙醇酸）组成。我们以前已经表明，这种持续的CCL 22从点源有效地招募调节性T细胞（TCLs）注射部位。在小鼠实验性牙周炎的牙龈中施用Treg募集制剂后，我们观察到标志性Treg相关抗炎分子增加，促炎细胞因子减少，牙槽骨吸收显着减少。此外，Treg募集制剂（用人CCL 22制备）在比格犬结扎诱导的牙周炎中的应用导致在存在不同牙周病原体环境的严重炎症条件下炎症的临床测量减少和牙槽骨损失减少。
The hallmark of periodontal disease is the progressive destruction of gingival soft tissue and alveolar bone, which is initiated by inflammation in response to an invasive and persistent bacterial insult. In recent years, it has become apparent that this tissue destruction is associated with a decrease in local regulatory processes, including a decrease of forkhead box P3-expressing regulatory lymphocytes. Accordingly, we developed a controlled release system capable of generating a steady release of a known chemoattractant for regulatory lymphocytes, C-C motif chemokine ligand 22 (CCL22), composed of a degradable polymer with a proven track record of clinical translation, poly(lactic-co-glycolic) acid. We have previously shown that this sustained presentation of CCL22 from a point source effectively recruits regulatory T cells (Tregs) to the site of injection. Following administration of the Treg-recruiting formulation to the gingivae in murine experimental periodontitis, we observed increases in hallmark Treg-associated anti-inflammatory molecules, a decrease of proinflammatory cytokines, and a marked reduction in alveolar bone resorption. Furthermore, application of the Treg-recruiting formulation (fabricated with human CCL22) in ligature-induced periodontitis in beagle dogs leads to reduced clinical measures of inflammation and less alveolar bone loss under severe inflammatory conditions in the presence of a diverse periodontopathogen milieu.