T-Regulatory Cells in Periodontitis

描述(由申请人提供)：拟议项目的目标是阐明最近发现的免疫抑制T细胞亚群，T调节(Treg)细胞在牙周致病适应性免疫反应(PPAIR)中的作用、机制和特征。Treg细胞不同于T效应细胞(Th1-、Th2-或Th17-细胞)，因为它们产生的细胞因子(IL-10和TGF-2)以及他们表达的独特的转录因子FOXP3，以及伴随表达的CD25。重要的是，众所周知，Treg细胞可以抑制自身免疫和传染病以及许多其他与免疫反应相关的结果中发生的获得性免疫反应。因此，通过我们的小鼠牙周病(PD)模型，成功地表征了Treg的分子免疫机制，我们将获得未来人类临床试验所需的理解。这一翻译策略应该导致开发新的无药物和无副作用的治疗方法来治疗人类牙周骨丢失和组织破坏，以及其他免疫相关的口腔疾病。一种这样的方法，UV照明，总结如下。我们最近发现，破骨细胞分化因子RANKL在牙周病患者的牙龈组织中由活化的T细胞和B细胞表达，而在健康牙龈组织中不表达，从而证明了获得性免疫反应的致病作用。我们最近发现，不表达RANKL的CD25+T细胞表达FOXP3的频率在牙周病患者的牙龈组织中显著低于健康牙周组织。在小鼠牙周病模型的基础上，我们的初步研究表明，过继转移CD25+Treg细胞，在体外用Treg开发因子-2扩增，可以改善PPAIR诱导的牙周骨丢失，并抑制Th1效应细胞的体外抗原特异性增殖及其产生RANKL。这些结论反过来又使我们推测，一般的紫外线照射，特别是UVB照射，可能在牙周病的治疗中具有新的治疗用途。也就是说，由于UVB在治疗银屑病(一种被认为是免疫介导的皮肤病)时用于增加Treg细胞的数量，因此同样的技术应该会上调小鼠牙龈上皮细胞转化生长因子-2的表达，导致牙龈中FOXP3+/CD25+Treg细胞的增加。这样一个先前优化的研究平台将使我们能够阐明迄今尚未研究的Treg细胞在牙周疾病中的作用、特征和机制。因此，在这个项目中，我们将研究1)Treg细胞在抑制PPAIR诱导的骨吸收中对抗原特异性的要求，2)Treg细胞在PPAIR诱导的牙周骨吸收中的作用和机制，以及3)开发一种有前景的光治疗帕金森病的方法，该方法利用牙周紫外线诱导Treg的现象。 项目简介：我们的研究将产生经验性数据，证实最近发现的免疫抑制淋巴细胞亚群T调节细胞(Treg)的流行率和活性。到目前为止，Treg的免疫抑制功能研究较少，其在牙周病原性适应性免疫反应(PPAIR)中的作用、机制和特点还没有研究过。因此，建议的项目将使用牙周病的小鼠模型以及牙周病的人类牙龈组织，以阐明我们对小鼠和Treg介导的免疫干预在帕金森病发病机制中的共性的理解。在某种程度上，这些结果是翻译的，我们可以开始开发新的治疗方法。其中一种有希望的治疗方式是以UVB照明的形式应用于病变组织的病变。这是构成我们研究基础的关键治疗策略。增强Treg活性与UVB照射治疗银屑病有关。因此，我们相信，我们为我们的小鼠体内模型计划的试验将被证明在诱导人类体内Treg方面同样有效，从而可能改善PPAIR的骨骼破坏效应。

DESCRIPTION (provided by applicant): The goal of the proposed project is to elucidate the roles, mechanisms and features of a recently discovered immune suppressive T cell subset, T regulatory (Treg) cells, in the context of periodontal pathogenic adaptive immune responses (PPAIR). Treg cells are distinct from T effector cells (Th1-, Th2- or Th17-cells) based on their profiles of cytokine production (IL-10 and TGF-2) as well as their expressions of a unique transcription factor, FOXP3, and concomitantly expressed CD25. Importantly, Treg cells are known to suppress adaptive immune responses occurring in autoimmune and infectious diseases and in many other immune-response related outcomes. Thus, upon successful characterization of Treg's molecular-immunological mechanisms, via our mouse model of periodontal disease (PD), we will have gained the understanding required for future human clinical trials. This translational strategy should lead to the development of novel drug-free and side- effect-free therapeutic approaches to the treatment human periodontal bone loss and tissue destruction, as well as other immune-associated oral diseases. One such approach, UV illumination, is summarized below. The pathogenic involvement of adaptive immune response was demonstrated by our recent discovery that the osteoclast differentiation factor, RANKL, is distinctively expressed by activated T cells and B cells in gingival tissues with periodontal disease, but not by these cells in healthy gingival tissues. We recently found that the prevalence of FOXP3 expression by CD25+ T cells, which do not express RANKL, was significantly lower in human gingival tissues with periodontal disease than in healthy tissues. Based on a mouse model of periodontal disease, our preliminary studies indicated that adoptive transfer of CD25+ Treg cells, which were ex vivo-expanded with Treg developing factor, TGF-2, could ameliorate the periodontal bone loss induced by PPAIR induction, as well as inhibit in vitro antigen-specific proliferation of Th1 effector cells and their production of RANKL. These conclusions have, in turn, led us to speculate that UV illumination in general, and UVB illumination in particular, could have a novel therapeutic use in the treatment of periodontal disease. That is, since UVB is used to augment the Treg cell population in the treatment of psoriasis, a skin disease hypothesized to be immune-mediated, then the same technique should up-regulate TGF-2 expression in mouse gingival epithelium, resulting in an increase of FOXP3+/CD25+ Treg cells in the gingivae. Such a previously optimized research platform will permit us to elucidate the as yet unstudied roles, features and mechanisms of Treg cells in the context of periodontal disease. Therefore, in the proposed project, we will investigate 1) the requirement of antigen specificity by Treg cells in their suppression function to PPAIR-induced bone resorption, 2) the roles and mechanisms of Treg cells on the regulation of PPAIR- induced periodontal bone resorption; and 3) the development of a promising phototherapeutic approach to PD, which utilizes the phenomenon of Treg induction by gingival UV illumination. PROJECT NARRATIVE: Our studies will generate empirical data confirming the prevalence and activity of a recently discovered immune suppressive lymphocyte subpopulation, T regulatory cells (Treg). To date, the immune suppressive function of Treg has only been sparsely studied, and its roles, mechanisms, and features, in terms of periodontal pathogenic adaptive immune response (PPAIR), have not been studied at all. Therefore, the proposed project will employ both a mouse model of periodontal disease, as well as periodontally diseased human gingival tissues, to illuminate our understanding of the commonalities between mouse and Treg-mediated immune intervention in the pathogenesis of PD. To the extent that these results are translational, we can begin to develop novel therapies. One such promising therapeutic modality is the application of phototherapy, in the form of UVB illumination, to the lesions of diseased tissue. This is the key therapeutic strategy that forms the foundation of our study. Augmentation of Treg-activity is implicated in the treatment of psoriasis by UVB illumination. Thus, we believe that the trials we plan for our mouse in vivo model will prove equally effective in inducing human in vivo Treg and thereby possibly ameliorating the bone destructive effects of PPAIR.