Loss of tolerance to enteric bacteria in pediatric IBD

尽管在过去的二十年中取得了显著的进展，但对炎症性肠病(IBD)的病因和机制的了解仍然不完整。一个重要的原因是，目前关于IBD发病机制的大部分研究都来自于患有晚期、长期疾病的成人患者。在这一人群中，早期的致病事件可能被时间和治疗所掩盖或修改，并且不再被检测到。相比之下，儿童早期的IBD可能仍然存在引发肠道炎症的异常。也有证据表明，正常的肠道菌群发挥着比之前想象的更重要的作用，无菌动物的结肠炎就证明了这一点。由于肠腔菌群在本质上是非致病的，IBD患者黏膜免疫系统对其的反应可能是异常的，可能是由于粘膜T细胞对肠道细菌抗原的耐受性丧失所致。类似的机制可能适用于人类，并存在于早发性IBD儿童中，其中对常驻菌群的耐受性丧失可能是一个关键的启动事件。因此，这项建议将结合对IBD儿童的研究和肠道细菌抗原特异性免疫反应性的研究来检验以下中心假设：儿童早期IBD是由于对正常肠道菌群的抗原失去耐受性所致，其持久性导致IBD的慢性化。这一假设将通过四个特定的目的来检验：目的1.调查正常肠道菌群对抗原的增殖反应和粘膜T细胞；目的2.确定正常肠道菌群抗原诱导的粘膜T细胞细胞因子；目的3.检测黏膜T细胞为正常肠道菌群产生抗原特异性抑制细胞的能力；目的4.比较确定的IBD患者组对正常肠道菌群的耐受性。这些研究将通过用来自自体的抗原和关于肠道T细胞功能异常的信息来攻击粘膜T细胞系和克隆来进行，出于治疗目的，这些T细胞功能可能对免疫调节敏感。

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.