CD26-inhibition for the prevention of chronic lung allograft rejection

慢性肺移植功能障碍(CLAD)是肺移植受者长期存活的主要障碍。慢性阻塞性肺疾病是小气道和肺实质进行性纤维化重塑的结果，临床表现为不可逆转的肺功能丧失。CLAD患者死亡率高，目前尚无针对CLAD的因果治疗方法。CD26是一种跨膜分子，具有调节移植后免疫反应的酶活性和共刺激活性。然而，CD26在器官纤维化的发生和发展中也起着关键作用。一些实验研究已经确认CD26促进纤维化的发展，越来越多的数据表明，当抑制CD26时，纤维化改变可以被消除。在这项建议中，我们的目标是通过(I)实验和(Ii)翻译-临床方法通过药物抑制CD26/DPP4来减轻甚至防止CLAD的发展：(I)我们评估了系统性CD26抑制在慢性排斥反应小鼠肺移植模型中发生CLAD期间的免疫调节和抗纤维化作用。此外，我们还将分析CD26抑制对移植血管内皮细胞缺血再灌注损伤的潜在保护作用，以防止与CLAD直接或间接相关的关键初始事件和炎性细胞内流。(Ii)在翻译-临床方法中，我们希望证明CD26抑制在人类慢性肺移植排斥反应中的作用。为此，我们将采用一种从肺移植受者的肺活检标本发展而来的体外球形细胞培养模型。这一模型将允许对CD26抑制在慢性肺移植排斥反应中的抗纤维化作用进行个体评估。CD26-抑制剂多年来作为抗糖尿病药物在临床上被常规使用，没有明显的副作用，从而促进了这些化合物作为其他疾病的治疗药物的重新用途。通过在两个高度相关和成熟的研究模型中研究CD26抑制的抗纤维化作用，我们将对抗CLAD的治疗获得实质性的新见解。这些数据将为一项临床试验奠定基础，该试验将CD26抑制剂重新用于肺移植患者的抗纤维化治疗。

Chronic lung allograft dysfunction (CLAD) is the major hurdle to long-term survival in lung transplant recipients. CLAD results from a progressive fibrotic remodeling of small airways and the lung parenchyma and clinically manifests as an irreversible loss of pulmonary function. Patients with CLAD have a high mortality and no causal therapy against CLAD is available up to now. CD26 is a transmembrane molecule with enzymatic and costimulatory activity regulating immune responses after transplantation. However, CD26 also has key functions in the initiation and progress of organ fibrosis. Several experimental studies have identified CD26 to promote the development of fibrosis, and increasing data suggest that when inhibiting CD26, fibrotic changes can be abrogated. In this proposal, we aim to attenuate or even prevent CLAD development by pharmacological inhibition of CD26/DPP4 by an (I) experimental and a (II) translational-clinical approach: (I) we evaluate the immunomodulatory and anti-fibrotic effects of systemic CD26 inhibition during the development of CLAD in a murine lung transplantation model of chronic rejection over time. Also, we will analyze for the potential protective effect of CD26-inhibition on transplant endothelium against ischemia-reperfusion injury to prevent key initial events and inflammatory cells influx directly and indirectly linked to CLAD. (II) In a translational-clinical approach, we wish to demonstrate the effects of CD26-inhibition in human chronic lung transplant rejection. To this end, we will employ an ex vivo spheroid cell culture model developed from pulmonary biopsy specimens from lung transplant recipients. This model will allow for an individual evaluation of the anti-fibrotic effect of CD26-inhibition in chronic lung allograft rejection. CD26-inhibitors are in routine clinical use as antidiabetics without significant side effects for many years, thus facilitating the repurpose of these compounds as therapeutics in other diseases. By studying the antifibrotic effect of CD26-inhibition in two highly relevant and established research models, we will gain substantial new insights into the therapy against CLAD. These data will then set the base for a clinical trial repurposing CD26-inhibitors as anti-fibrotic therapeutics in lung transplanted patients.