Mechanistically based therapeutic strategies in murine primary biliary cholangitis

总结 原发性胆汁性胆管炎（PBC）的治疗一直落后于其他自身免疫性疾病。我们提出 我们的多学科团队在代谢组学、免疫学、分子生物学、 生物学和病理学。我们认为，我们使用的ARE-/-小鼠是一个强大的新模型，因为小鼠重演 女性占优势的人PBC、AMA、门静脉炎症、总胆汁酸增加、瘙痒、纤维化 和TLR 7介导的功能所需的I型干扰素（IFN）的女性表达升高。我们将首先 提出了一种全新的治疗自身免疫的方法，在这种方法中， 与肠道微生物组代谢物疗法组合恢复耐受性。自身免疫性肝病是理想的 因为肝脏位于结肠的上游。事实上，如果去除致病细胞， 通过致耐受性饮食在PBC中起作用（我们的目标1），它应该会导致其他自身免疫性疾病的试验。Th 1或Th 17 细胞去除是一种激进的新方法，重要的是要补充这与了解个人 Th 1或Th 17/Tfh/生发中心通路分子，以了解Th 1或Th 17生物学是否支持 PBC。我们将通过调节TLR 7下调效应子功能并改变其表达水平， 中枢功能（Aim 2）和/或直接处理IFN受体信号传导（Aim 3）。这些目标是 基于我们的数据和独特的资源，直接针对自身免疫性胆管炎的机制。我们 研究小组拥有丰富的已发表/未发表的数据，包括在调节自身免疫方面的丰富经验 通过饮食和代谢物。因此，我们的三个目标是首先通过抗体耗竭消除致病细胞 Th 1（CXCR 3 mAb）或Th 17和Tfh（CCR 6 mAb），然后进行免疫恢复/调节， 细菌代谢物，提高THBE和促进耐受性。该步骤涉及使用HAMS（高直链淀粉 玉米淀粉）饮食，其产生非常大量的肠丁酸盐或乙酸盐。这种方法已经奏效 在NOD小鼠的糖尿病研究中，我们的第二个目标是调节TLR 7，这对于 GC形成，并预防雌性ARE-/-小鼠的疾病; TLR 7在雌性ARE-/-小鼠中高度表达。 这些数据可能会导致未来使用靶向TLR 7信号传导的小分子的机会。在我们的第三和 最终目的我们提出抑制I型IFN受体信号传导将是治疗性的。我们知道删除 ARE-/-小鼠中的I型IFN受体降低了疾病的严重程度。因此，我们将用mAb阻断IFN受体， 和JAK/STAT信号传导与JAK抑制剂。我们共同认为，这项建议是创新的，可能会导致 更好的治疗方法，不仅在PBC中，而且在其他自身免疫性疾病中也具有重要意义。 疾病

Summary The treatment of primary biliary cholangitis (PBC) has lagged behind other autoimmune diseases. We propose to challenge this void with our multidisciplinary team with expertise in metabolomics, immunology, molecular biology and pathology. We submit that our use of ARE–/– mice are a powerful new model as mice recapitulate human PBC with female predominance, AMAs, portal inflammation, increased total bile acids, itching, fibrosis and elevated female expression of type I interferon (IFN), required for TLR7 mediated function. We will first propose an entirely new approach to treat autoimmunity, in which depletion of pathogenic immune cells in combination with gut microbiome metabolite therapy restores tolerance. Autoimmune liver diseases are ideal for such therapies because the liver is situated upstream from the colon. Indeed, if pathogenic cell removal, followed by tolerogenic diets work in PBC (our Aim 1), it should lead to trials in other autoimmune diseases. Th1 or Th17 cell removal is a radical new approach, and it is important to complement this with understanding of individual Th1 or Th17/Tfh/germinal centre pathway molecules, to understand whether Th1 or Th17 biology underpins PBC. We will address pathway involvement by downregulating effector function by modulating TLR7 and altering germinal center function (Aim 2) and/or directly addressing IFN receptor signaling (Aim 3). These goals are based on our data, and unique resources that directly target the mechanisms of autoimmune cholangitis. Our group has a wealth of published/unpublished data including extensive experience in modulating autoimmunity by diet and metabolites. Hence our three goals are firstly to eliminate pathogenic cells through antibody depletion of Th1 (CXCR3 mAb), or Th17 and Tfh (CCR6 mAb), followed by immune restoration/regulation with beneficial bacterial metabolites that boost Tregs and promote tolerance. This step involves use of HAMS (high amylose maize starch) diets that produce very large amounts of gut butyrate or acetate. This approach has worked spectacularly well in our hands for diabetes in the NOD mouse. Our second goal is to modulate TLR7, critical for GC formation, and prevent disease in female ARE–/– mice; TLR7 is highly expressed in female ARE–/– mice. These data may lead to future opportunities using small molecules that target TLR7 signaling. In our third and final aim we propose that inhibition of type I IFN receptor signaling will be therapeutic. We know that deletion of the type I IFN receptor in ARE–/– mice reduces disease severity. Thus, we will block the IFN receptor with a mAb and JAK/STAT signaling with a JAK inhibitor. Collectively we submit that this proposal is innovative, likely to lead to better therapeutic approaches, and has importance not only in PBC but generically in other autoimmune diseases.