Developmental trajectory and function of Th10 cells in IBD

IBD是一种毁灭性的疾病，患者会经历剧烈的疼痛，从而严重限制了他们的日常生活。近年来出现了新的治疗方法。然而，只有大约一半的患者达到疾病的缓解（治疗上限），随着时间的推移，高达40%的患者失去疗效，只有极少数患者出现耐受状态，允许他们停药。最后，IBD发病率正在增加，特别是在工业化国家。考虑到所有这些，迫切需要更好地了解促进IBD的分子和细胞机制。这些知识将为未来能够“打破IBD治疗上限”的治疗奠定基础。 我们和其他人已经提出，CD 4 + T细胞，特别是Th 1和Th 17细胞，在IBD中起着至关重要的作用。细胞因子IL-12和IL-23促进这些细胞的出现和致病性。因此，阻断这些细胞因子的抗体在相当大部分的IBD患者中诱导并维持缓解。然而，如上所述，目前的治疗在约一半的患者中诱导缓解。部分IBD患者无反应的原因尚不清楚。我们提出，还有其他的，到目前为止，未被识别的CD 4 + T细胞群，这不是目前治疗的目标，并有助于肠道炎症。在第一个资助期，我们意外地发现产生IL-10的Foxp 3-CD 4 + T细胞也包括促炎亚群，称为Th 10细胞。事实上，初步数据显示，Th 10细胞在IBD患者中富集，并且具有在小鼠IBD模型中诱导结肠炎的潜力。基于此，我们假设Th 10细胞驱动IBD。我们将通过分析IBD患者在生物治疗前后来验证这一假设。此外，我们将使用已建立的和新的小鼠模型来验证体内Th 10细胞的发育轨迹、代谢和致病潜力。在这方面的工作，它将使我们能够发现解释IBD致病性的新参与者，并且作为一个长期目标，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.