Loss of tolerance to enteric bacteria in pediatric IBD

尽管在过去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是基于晚期、长期疾病的成年患者。在这一人群中，早期致病事件可能因时间和治疗而被掩盖或改变。，并且无法被发现。相反，儿童早期IBD可能仍然存在引起肠道炎症的异常。也有证据表明，正常肠道菌群发挥的作用远比以前设想的重要，这一点在无菌动物中没有结肠炎。由于肠道菌群本质上是非致病性的，黏膜免疫系统对它的反应可能在IBD中是异常的，这可能是由于粘膜t细胞对肠杆菌抗原的耐受性丧失。类似的机制可能适用于人类和早发性IBD儿童，其中对常驻菌群的耐受性丧失可能是一个关键的起始事件。因此，本研究将对儿童IBD的研究与肠道细菌抗原特异性免疫反应性的研究结合起来，以验证以下中心假设：儿童早期IBD是由于对正常肠道菌群抗原的耐受性丧失，其持续存在导致IBD的慢性。这一假设将通过四个具体目标来检验：目标1。探讨粘膜t细胞对正常肠道菌群抗原的增殖反应；目标2。定义由正常肠道菌群抗原诱导的粘膜t细胞因子；目标3。检查粘膜t细胞为正常肠道菌群产生抗原特异性抑制细胞的能力；目标4。比较特定组IBD患者与正常肠道菌群的耐受性。这些研究将通过挑战粘膜t细胞系和克隆，使用来自自体的抗原和肠道t细胞功能异常的信息，这些信息可能对免疫调节敏感，以达到治疗目的。

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.