Regulatory T Cells and Pulmonary Hypertension

项目摘要/摘要 临床和临床前研究表明，自身免疫和慢性炎症是由异常引起的 在调节性T细胞(Treg)中，参与了肺动脉高压的发生发展 (PAH)。Treg功能障碍对男性和女性的影响不同，可能是由致病基因引起的 变异和发炎的组织微环境。Treg输注作为一种基于细胞的治疗方法，可以恢复免疫力 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单等位基因突变与肺 炎症会引发严重的疾病。在这些Bmpr2突变动物中，以及无瘤大鼠的疾病模型中， PAH的易感性可能与Treg的发育和功能异常有关。从基因上注入- 纠正(Bmpr2野生型)Tregs进入Bmpr2突变动物，或将Tregs注射到无瘤大鼠，恢复 免疫调节，防止血管重塑，改善PAH。多项Treg输注的临床试验 正在接受自身免疫和炎症条件的测试，并已显示出早期的希望。考虑到未来 Treg疗法在治疗人类PAH方面的潜力，这一建议检验了遗传和 环境线索触发可加重PAH和Treg功能恢复的Treg异常可能是 足以逆转严重疾病。 这项建议调查了遗传(BMPR2突变)和环境(肺部炎症)风险 Treg基因紊乱和易患PAH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见文献记载的BMPR2信号在 适应性免疫细胞(即树突状细胞)。特异靶1评估PAH中Treg免疫的机制 受Bmpr2突变、慢性肺部炎症和性相关因素的影响。特定目标1有两个 研究胸腺Treg发育的子目标(目标1a)和肺Treg的表型和功能(目标1b) 在PAH。通过了解Treg输注如何平息肺部炎症和预防血管损伤， 目的2开发使用体外扩张的Tregs治疗已建立的PAH的方案。《特定目标2》有三个 子目标，首先建议标记和跟踪收养转移后注入的Treg(目标2a)，然后评估 Treg对肺血管细胞的保护作用(目标2b)，最后，测试不同类型药物的疗效 Treg输注策略逆转晚期PAH(Aim 2c)。这些研究有助于统一遗传学的概念 易损性和免疫失调是导致PAH的相关危险因素，这可能提供明确的 未来治疗途径的方向，尤其是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.