Loss of tolerance to enteric bacteria in pediatric IBD

尽管在过去的二十年中取得了重大进展，但对炎症性肠病（IBD）的病因和机制的认识仍然不完整。一个重要的原因是，目前IBD发病机制知识的大部分研究都是基于患有晚期、长期疾病的成年患者。在这一人群中，早期致病事件可能被时间和治疗所掩盖或改变。并且不再被发现。相比之下，儿童早期IBD可能仍然存在引发肠道炎症的异常。也有证据表明，正常的肠道植物群发挥的作用比以前设想的要重要得多，如无菌动物中没有结肠炎所示。由于腔内植物群本质上是非致病性的，因此IBD中粘膜免疫系统对其的应答可能是异常的，这可能是由于粘膜T细胞对肠细菌抗原的耐受性丧失。类似的机制可能在人类中起作用，并存在于患有早发性IBD的儿童中，其中对常驻植物群的耐受性丧失可能是关键的起始事件。因此，本提案将IBD儿童研究与肠道细菌抗原特异性免疫反应性研究相结合，以检验以下中心假设：儿童早期IBD是由于对正常肠道植物群抗原的耐受性丧失，其持续性导致IBD慢性化。这一假设将通过四个具体目标进行检验：目标1。目的2.研究正常肠道植物群抗原对粘膜T细胞增殖反应的影响。定义正常肠道植物群抗原诱导的粘膜T细胞细胞因子;目的3.检查粘膜T细胞产生正常肠道植物群的抗原特异性抑制细胞的能力;目的4.在确定的IBD患者组中比较对正常肠道植物群的耐受性。这些研究将通过用自体来源的抗原挑战粘膜T细胞系和克隆以及可能易受治疗目的免疫调节影响的肠道T细胞功能异常的信息进行。

In spite of significant progress during the last two decades, knowledge of the cause and mechanisms of inflammatory bowel disease (IBD) is still incomplete. An important reason is that the bulk of studies of which current knowledge of IBD pathogenesis is based derived from adult patients with late, longstanding disease. In this population, early pathogenic events may be concealed or modified by time and therapy., and no longer detectable. In contrast, early IBD in children may still harbor the abnormalities responsible for triggering intestinal inflammation. There is also evidence that normal enteric flora plays a far more important role than previously envisioned, as shown by the absence of colitis in germfree animals. Since luminal flora is intrinsically non pathogenic, the response of the mucosal immune system against it might be abnormal in IBD, perhaps due to a loss of tolerance to enterobacterial antigens by mucosal T-cells. A similar mechanism may be operative in humans and present in children with early onset IBD where loss of tolerance to resident flora may be a critical initiating event. Therefore, this proposal will integrate studies of children with IBD with studies of enteric bacterial antigen-specific immune reactivity to test the following central hypothesis: Early IBD in children results from loss of tolerance to antigens of the normal enteric flora, and its persistence lead to chronicity of IBD. This hypothesis will be tested by four specific aims: Aim 1. Investigate the proliferative response and mucosal T-cells to antigens of the normal enteric flora; Aim 2. Define mucosal T-cell cytokines induced by antigens of the normal enteric flora; Aim 3. Examine mucosal T-cell capacity to generate antigen-specific suppressor cells for the normal enteric flora; Aim 4. Compare tolerance to normal enteric flora in defined groups of IBD patients. These studies will be performed by challenging mucosal T-cell lines and clones with antigens derived from autologous and information on abnormalities of intestinal T-cell function that may be susceptible to immunomodulation for therapeutic purpose.