Regulatory T Cells and Pulmonary Hypertension

项目概要/摘要 临床和临床前研究表明，异常引起的自身免疫和慢性炎症 在调节性T细胞（T细胞）中，有助于肺动脉高压的发生和进展 （PAH）。Treg功能障碍对男性和女性的影响不同， 变体和发炎的组织微环境。Treg输注作为一种基于细胞的疗法， 调节，减少血管炎症，并防止动物发展PAH。在一种新的转基因大鼠中， 遗传性PAH模型，骨形态发生蛋白受体2（Bmpr 2）和肺中的单等位基因突变 炎症引起严重疾病。在这些Bmpr 2突变动物以及无胸腺大鼠疾病模型中， PAH易感性可能与Treg发育和功能异常有关。注入基因- 将校正的（Bmpr 2野生型）Tcl 4注射入Bmpr 2突变体动物，或将Tcl 4注射入无胸腺大鼠， 免疫调节，防止血管重塑和改善PAH。一些Treg输注临床试验 正在接受自身免疫和炎症状况的测试，并已显示出早期的希望。考虑到未来 Treg疗法在治疗人类PAH中的潜力，该提案测试了遗传和 环境因素触发Treg异常，加重PAH，Treg功能的恢复可能是 足以逆转严重的疾病。 这项提案调查了遗传（BMPR 2突变）和环境（肺部炎症）风险 导致Treg紊乱和PAH易感性的因素，以及Treg输注如何限制血管 损伤和逆转PAH。拟议的研究解决了以前未记录的BMPR 2信号转导在 适应性免疫细胞（即，Tennis）。具体目标1评价了PAH中Treg免疫的机制 受Bmpr 2突变、慢性肺部炎症和性相关因素的影响。具体目标1有两个 研究胸腺Treg发育（Aim 1a）和肺Treg表型和功能（Aim 1b）的子目标 在PAH中。通过了解Treg输注如何平息肺部炎症并预防血管损伤， 目的2：制定使用体外扩增TdR治疗已确诊PAH的方案。第2章有三个目标 子目标，首先提出在过继转移后标记和跟踪输注的TdR（目标2a），然后评估 Treg对肺动脉血管细胞的保护作用（目的2b），并且最后，为了测试各种治疗的功效， 逆转晚期PAH的Treg输注策略（目的2c）。这些研究有助于统一遗传学概念， 脆弱性和免疫失调作为诱发PAH的相关风险因素，这可能提供明确的 未来治疗途径的方向，特别是Treg免疫疗法。

PROJECT SUMMARY / ABSTRACT Clinical and preclinical studies indicate that autoimmunity and chronic inflammation, resulting from abnormalities in regulatory T cells (Tregs), contribute to the development and progression of pulmonary arterial hypertension (PAH). Treg dysfunction affects males and females differently and may arise because of pathogenic gene variants and an inflamed tissue microenvironment. Treg infusion, as a cell-based therapy, restores immune regulation, reduces vascular inflammation, and prevents animals from developing PAH. In a novel transgenic rat model of hereditary PAH, monoallelic mutations in bone morphogenetic protein receptor 2 (Bmpr2) and lung inflammation elicit severe disease. In these Bmpr2 mutant animals, as well as the athymic rat model of disease, the predisposition to PAH may relate to abnormal Treg development and function. Infusion of genetically- corrected (Bmpr2 wildtype) Tregs into Bmpr2 mutant animals, or injection of Tregs into athymic rats, restores immune regulation, prevents vascular remodeling and ameliorates PAH. A number of Treg-infusion clinical trials are being tested for autoimmune and inflammatory conditions and have shown early promise. Given the future potential of Treg therapy in treating human PAH, this proposal tests the hypothesis that genetic and environmental cues trigger Treg abnormalities that exacerbate PAH and that restoration of Treg function may be sufficient to reverse severe disease. This proposal investigates how genetic (BMPR2 mutations) and environmental (pulmonary inflammation) risk factors contribute to Treg derangements and a predisposition to PAH, and how Treg infusion can limit vascular injury and reverse PAH. Proposed studies address a previously undocumented role of BMPR2 signaling in adaptive immune cells (i.e., Tregs). Specific Aim 1 evaluates the mechanisms by which Treg immunity in PAH is affected by Bmpr2 mutations, chronic lung inflammation and sex-related factors. Specific Aim 1 has two subaims which study thymic Treg development (Aim 1a) and pulmonary Treg phenotype and function (Aim 1b) in PAH. By understanding how Treg infusion quells lung inflammation and prevents vascular injury, Specific Aim 2 develops protocols to use ex vivo-expanded Tregs to treat established PAH. Specific Aim 2 has three subaims which first proposes to label and track infused Tregs after adoptive transfer (Aim 2a), then to assess Treg protective effects on pulmonary arterial vascular cells (Aim 2b), and, finally, to test the efficacy of various Treg infusion strategies in reversing advanced PAH (Aim 2c).These studies help unify the concepts of genetic vulnerability and immune dysregulation as related risk factors predisposing to PAH, which may offer clear directions for future therapeutic avenues, most especially Treg immunotherapy.