Developmental trajectory and function of Th10 cells in IBD

IBD是一种毁灭性的疾病，患者经历严重的疼痛，因此在日常生活中受到严重限制。在过去的几年里，已经有了新的治疗方法。然而，只有大约一半的患者实现了疾病的缓解(治疗上限)，随着时间的推移，最多有40%的患者失去了疗效，只有极少数患者达到了允许他们停药的耐受状态。最后，IBD的发病率正在增加，特别是在工业化国家。考虑到这一切，迫切需要更好地了解促进IBD的分子和细胞机制。这一知识将为未来能够“打破IBD治疗天花板”的治疗奠定基础。我们和其他人提出，CD4+T细胞，特别是Th1和Th17细胞，在IBD中起着至关重要的作用。细胞因子IL-12和IL-23促进这些细胞的产生和致病。因此，阻断这些细胞因子的抗体在相当一部分IBD患者中诱导和维持缓解。然而，如上所述，目前的治疗方法使大约一半的患者病情缓解。部分IBD患者没有反应的原因尚不清楚。我们认为，到目前为止，还有其他未被识别的CD4+T细胞群，它们不是当前治疗的靶点，而是导致肠道炎症的原因。在第一个资助期，我们出人意料地发现，产生IL-10的Foxp3-CD4+T细胞也包括促炎亚群，即Th10细胞。事实上，初步数据显示，在IBD患者中，Th10细胞丰富，并有可能在小鼠IBD模型中诱发结肠炎。在此基础上，我们假设Th10细胞驱动IBD。我们将通过分析IBD患者在生物治疗前后的情况来检验这一假设。此外，我们将使用已建立的和新的小鼠模型在体内验证Th10细胞的发育轨迹、代谢和致病潜力。在这方面的工作，将使我们能够发现解释IBD致病性的新参与者，并作为一个长期目标，也是未来IBD治疗的新目标。

IBD is a devastating disease, and patients experience sever pain and thus severe limitations in their daily life. New therapies have been become available in the last years. Yet only about half of the patients achieve remission of the disease (therapeutic ceiling), up to 40% loss efficacy over time and only very few patients develop a status of tolerance allowing them to withdraw the medication. Finally, IBD incidence is increasing especially in industrialized countries. Considering all this, there is an urgent need to better understand the molecular and cellular mechanisms promoting IBD. This knowledge will set the basis for future therapies able to “break the IBD therapy ceiling”. We and others have proposed that CD4+ T cells, in particular Th1 and Th17 cells, play a crucial role in the IBD. The cytokines IL-12 and IL-23 promote the emergence and the pathogenicity of these cells. Accordingly, antibodies blocking these cytokines induce and maintain remission in a significant fraction of IBD patients. Yet, as reported above, current therapies induce remission in about half of the patients. The reason why part of the IBD patients do not respond is unclear. We propose that there are other, and so far, unrecognized CD4+ T-cell populations, which are not targeted by the current therapies and contribute to intestinal inflammation. In the first funding period we found unexpectedly that IL-10-producing Foxp3- CD4+ T cells include also a pro-inflammatory subpopulation, which are referred to as Th10 cells. Indeed, preliminary data show that Th10 cells are enriched in IBD patients and have the potential to induce colitis in a mouse IBD model. Based on this we hypothesise that Th10 cells drive IBD. We will test this hypothesis by analysing IBD patients before and after biological therapies. Furthermore, we will use established and new mouse models to validate in vivo the developmental trajectory, metabolism, and pathogenic potential of Th10 cells. Working on this aspect, it will allow us to discoverer new players explaining the pathogenicity of IBD and, as a long-term goal, also new targets for future IBD therapies.