Validation of novel immunotherapeutic targets against fibrosis in inflammatory bowel diseases

纤维狭窄是炎性肠病（IBD）患者持续需要肠切除术的主要原因。目前的IBD治疗仅限于仅针对炎症。虽然这些治疗在一些（但不是全部）病例中导致症状性疾病缓解，但在缓解期之间的复发性耀斑仍将导致累积的肠壁重塑和纤维化。事实上，尽管有这些治疗策略来控制炎症，纤维狭窄的发生率和肠手术切除在IBD患者中并没有下降，因为目前没有抗纤维化药物可用。该项目的目的是验证ibd患者样本中预防和/或治疗纤维化的成纤维细胞治疗靶点，重点关注肠纤维化演变中的C3和/或Tyk2/STAT3和/或NLRP3。这些新型免疫疗法的抗纤维化功效和作用模式将在ibd患者衍生样本中进行临床前研究，并在慢性结肠炎动物模型中进行验证。同时，我们的目标是开发和验证IBD患者纤维化的临床诊断和预后途径，该途径基于使用非侵入性横断面成像技术，如磁共振肠图与弹性成像和光声学。这些结果将允许设计针对肠道纤维狭窄补体C3和/或Tyk2/STAT3和/或NLRP3途径的免疫治疗药物的首次人体概念验证随机试验。我们的目标是获得患者和监管部门的批准，将这些新型的非侵入性成像方式作为纤维化性IBD的诊断和预后工具，从而促进肠道纤维化治疗的重要未来发展。通过对有纤维化风险的IBD患者提供更好的分子和临床分层，以及通过识别和验证抗纤维化治疗的新靶点，我们的目标是为预防和治疗这种无效的IBD合并症铺平道路。

Fibrostenosis is the driving reason for the persistent need in bowel resections in inflammatory bowel diseases (IBD). Current IBD therapies are limited to solely targeting inflammation. While these therapies in some, but not all, cases lead to symptomatic disease remission, recurrent flares interspaced with periods of remission will still result in cumulative gut wall remodeling and fibrosis. Indeed, despite these therapeutic strategies to control inflammation, fibrostenosis incidence and bowel surgical resection is not declining in IBD patients, as no anti-fibrotic drugs are currently available. The aim of this project is to validate fibroblast therapeutic targets for preventing and/or treating fibrosis in IBD-patient-samples with an emphasis on C3 and/or Tyk2/STAT3 and/or NLRP3 in the evolution of intestinal fibrosis. The anti-fibrotic efficacy and mode of action of these novel immunotherapies will be studied preclinically in IBD-patient derived samples and validated in animal models of chronic colitis. In parallel, we aim to develop and validate a clinical diagnostic and prognostic pathway for fibrosis in IBD patients based on the use of non-invasive cross-sectional imaging techniques such as magnetic resonance enterography with elastography and optoacoustic. These results together will allow to design a first-in-human proof of concept randomized trial of immunotherapeutic drugs targeting complement C3 and/or Tyk2/STAT3 and/or NLRP3 pathways in intestinal fibrostenosis. Our aim is to obtain patients and regulatory approval for implementation of these novel non-invasive imaging modalities as diagnostic and prognostic tools for fibrotic IBD to allow vital future therapeutic development for intestinal fibrosis. By providing better molecular and clinical stratification of IBD patients at risk for fibrosis and by identifying and validating novel targets for anti-fibrotic therapy, we aim to pave the way in preventing and treating this invalidating IBD comorbidity.