Loss of tolerance to enteric bacteria in pediatric IBD

点击翻译按钮获取中文摘要

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.