Innate Immune Aspects of Ocular Surface Disease

 描述（由申请人提供）：众所周知，眼表炎症在干眼病（DED）症状发展和扩大中起着重要作用。我们的实验室已经发现，许多中性粒细胞存在于患有严重泪液缺乏型DED亚型的患者的眼表面上，并且它们释放它们的核染色质复合物作为一种生物“蜘蛛网”。这些细胞外DNA（eDNA）网被称为中性粒细胞细胞外陷阱（NET）。虽然NET是先天免疫防御的一部分，但它们可能有助于慢性炎症性疾病如类风湿性关节炎和系统性红斑狼疮的病理学。我们发现，在严重的泪液缺乏性DED患者中，包括慢性眼移植物vs.在oGVHD患者中，在眼表面上存在过量的细胞外DNA（eDNA）和中性粒细胞细胞外陷阱（NET）的分子组分。NET在DED患者的眼表面上积聚，这是因为形成增加（由于高渗性）和/或清除减少（由于泪液缺乏和随之而来的核酸酶缺乏）。根据我们的数据，我们假设减少眼表中性粒细胞及其细胞外产物（eDNA和NET）丰度的临床策略有可能减少泪液缺乏性DED的体征和症状。为了检验这一假设，我们将使用临床终点进行I/II期、随机、双盲临床试验，以确定重组人DNA酶I滴眼液在72例因oGVHD（特异性目的A）导致泪液缺乏性DED患者中的治疗潜力。我们将前瞻性随访接受异基因造血干细胞移植（HSCT）的患者，并确定泪液成分（eDNA丰度和核酸酶活性）和外周血中性粒细胞（NET形成和趋化性）的变化是否可用于预测oGVHD（特异性目的B）的发生和进展。这项研究可能会导致开发一种新的oGVHD治疗方法-这种疾病极大地影响HSCT后的生活质量，并且没有特定的治疗方法。识别生物标志物对于预测哪些患者在HSCT后发生oGVHD的高风险至关重要，这种能力可能有助于设计个性化的治疗策略。

 DESCRIPTION (provided by applicant): It is well recognized that ocular surface inflammation plays a prominent role in dry eye disease (DED) symptom development and amplification. Our laboratory has discovered that numerous neutrophils are present on the ocular surface of patients with severe tear-deficient DED subtypes and that they release their nuclear chromatin complex as a type of biologic "spider's web". These extracellular DNA (eDNA) webs are termed neutrophil extracellular traps (NETs). Although NETs are part of the innate immune defense, they may contribute to pathology of chronic inflammatory diseases like rheumatoid arthritis and systemic lupus erythematosus. We showed that in severe tear-deficient DED patients, including chronic ocular graft-vs.-host- disease (oGVHD) patients, there were excessive amounts of extracellular DNA (eDNA) and molecular components of neutrophil extracellular traps (NETs) over the ocular surface. NETs accumulate on the ocular surface of DED patients either because of increased formation (due to hyperosmolarity) and/or reduced clearance (due to tear deficiency and consequent nuclease deficiency). Based on our data, we hypothesize that clinical strategies that reduce the abundance of neutrophils and their extracellular products (eDNA and NETs) on the ocular surface have the potential to reduce signs and symptoms of tear-deficient DED. To test this hypothesis, we will perform a phase I/II, randomized, double masked clinical trial using clinical endpoints to determine the therapeutic potential of recombinant human DNase I eye drops in 72 patients with tear-deficient DED due to oGVHD (Specific Aim A). We will prospectively follow patients who receive allogeneic hematopoietic stem cell transplant (HSCT) and determine if the changes that occur in tear fluid components (eDNA abundance and nuclease activity) and peripheral blood neutrophils (formation of NETs and chemotaxis) can be used to predict onset and progression of oGVHD (Specific Aim B). This research may lead to the development of a novel therapy for oGVHD - a condition that greatly impacts quality of life after HSCT and for which no specific therapies exist. Identifying biomarkers will be crucial for predicting which patients are at high risk for developing oGVHD after HSCT and this ability may help in designing personalized treatment strategies.