T cell response in scleroderma lung disease: from pathogenesis to clinical care

描述（由申请人提供）：这个职业发展奖的主要目标是获得技能和专业知识，成为风湿性疾病领域的独立研究者。这将通过在约翰霍普金斯大学流变学系进行一段时间的密集教学和研究培训来实现。该提案将研究量化效应T细胞极化（1型/2型）和自身抗原-拓扑异构酶-1（topo-1）-特异性T细胞作为硬皮病（SSc）患者的大型前瞻性队列中的肺病活动性和临床结果的预测因子的测量值。肺受累是目前SSc患者发病率和死亡率的主要原因。间质性肺病（ILD）是最常见的肺部表现。实验和临床研究表明，SSc中的肺纤维化可能是由促纤维化Th 2/Tc 2极化免疫应答引起的，并且涉及抗原驱动的T细胞活化。迄今为止，没有一种单一的测试可靠地预测肺纤维化的进展。我们的初步研究表明，循环T细胞的Th 2/Tc 2极化与ILD的存在显着相关，并且topo-1特异性CD 8 + T细胞在活动性肺泡炎患者的肺部中扩增。我们假设：（i）T细胞应答向Th 2/Tc 2表型的演变对于肺纤维化的发展至关重要，可能是SSc-ILD的早期标志物;（ii）Th 2/Tc 2促纤维化T细胞群在活动性ILD患者的肺中扩增，定量预测疾病进展的速率和严重程度;（iii）活动性ILD期间topo-1特异性T细胞应答的扩增与疾病活动性定量相关并预测临床结果。目的#1将在一个明确定义的SSc患者的大型前瞻性队列中研究T细胞极化的演变及其与ILD发生的相关性。约翰霍普金斯硬皮病中心将在整个项目期间提供专门的临床和研究支持。具体目标#2将确定具有Th 2/Tc 2极化表型的T细胞是否在活动性ILD患者的肺中富集并在肺纤维化的发病机制中发挥作用。将在因疑似活动性ILD接受支气管镜检查的队列患者（Aim 1）的血液和BAL液中测量Th 2/Tc 2 T细胞极化，并将其与随后的肺部疾病病程和结局相关联。具体目标#3将定义活动性ILD SSc患者血液和BAL中的topo-1特异性T细胞定量是否可以准确测量活动性并预测疾病结局。相关性：该项目的目标是确定SSc患者免疫应答的幅度和特征与特定临床表型（如肺纤维化）的发展之间是否存在直接联系。这可能允许识别疾病活动的更可靠的标志物，更好的预后预测因子和潜在的新的Ssc特异性治疗靶点。

DESCRIPTION (provided by applicant): The primary objective of this career development award is to acquire the skills and expertise to become an independent investigator in the field of rheumatic diseases. This will occur through a period of intense didactic and research training in the Division of Rheumatology at the Johns Hopkins University. This proposal will investigate the value of quantifying effector T cell polarization (type 1/type 2) and autoantigen- topoisomerase-1 (topo-1)-specific T cells as measures of lung disease activity and predictors of clinical outcomes in a large prospective cohort of scleroderma (SSc) patients. Lung involvement is currently the leading cause of morbidity and mortality in SSc patients. Interstitial lung disease (ILD) is the most common pulmonary manifestation. Experimental and clinical studies suggest that pulmonary fibrosis in SSc may result from a pro-fibrotic Th2/Tc2 polarized immune response and that an antigen-driven T cell activation is involved. To date, no single test reliably predicts progression towards lung fibrosis. Our preliminary studies suggest that Th2/Tc2 polarization of circulating T cells is strikingly associated with presence of ILD and that topo-1-specific CD8+ T cells are expanded in the lungs of patients with active alveolitis. We hypothesize that (i) the evolution of T cell responses towards a Th2/Tc2 phenotype is critical for the development of lung fibrosis and may be an early marker for SSc-ILD; (ii)the Th2/Tc2 pro-fibrotic T cell population is expanded in the lungs of patients with active ILD, quantitatively predicting rate and severity of disease progression;(Hi) amplification of the topo-1-specific T cell response during active ILD is quantitatively correlated with disease activity and predict clinical outcomes. Aim #1 will study the evolution of T cell polarization and its relevance to the development of ILD in a large prospective cohort of well-defined SSc patients. The Johns Hopkins Scleroderma Center will provide dedicated clinical and research support for the entire duration of the project. Specific Aim #2 will determine whether T cells with Th2/Tc2 polarized phenotype are enriched in the lungs of patients with active ILD and play a role in the pathogenesis of lung fibrosis. Th2/Tc2 T cell polarization will be measured in the blood and BAL fluid of the cohort patients (Aim1) undergoing bronchoscopy for suspected active ILD and correlated with the subsequent course of lung disease and outcome. Specific Aim #3 will define if topo-1-specific T cells quantification in the blood and BAL of SSc patients with active ILD can accurately measure activity and predict disease outcomes. Relevance: The goal of this project is to determine whether a direct link exists between the magnitude and features of the immune response in SSc patients and the development of specific clinical phenotypes such as lung fibrosis. This may allow the identification of more reliable markers for disease activity, of better predictors of outcome and potentially of novel SSc-specific therapeutic targets.