Immunobiology of Dendritic Cells in Crohn's Disease

描述(申请人提供)：巨噬细胞和树突状细胞(DC)对摄入的抗原和管腔微生物的反应的调节是肠粘膜内动态平衡的关键组成部分。我们已经报道，由于暴露于粘膜基质细胞产物，特别是转化生长因子-β(Smythies，et al.)，正常人类肠道中的驻留巨噬细胞的炎症反应显著下调(Smythies，et al.J·克莱恩。投资。115：66，‘05)。这种下调可能是导致正常小肠几乎没有炎症的原因。在肠道DC方面，我们的初步结果表明，与克罗恩病患者非炎症黏膜中的DC相比，正常人小肠粘膜中的常驻DC较少，表达较低的成熟和激活标志物，释放较低水平的细胞因子。因此，正常肠粘膜中的DC，如肠巨噬细胞，其炎症活性可能下调，提示肠道DC也是导致正常肠粘膜低水平炎症的原因之一，克罗恩病患者非炎症性肠粘膜中的DC可能不那么严格地下调，从而能够促进炎症。我们的初步结果表明，肠道固有层基质释放的因子下调单核细胞来源的DC(M-DC)的成熟度和炎症潜能，这表明可能是一种机制，使可能来自循环的肠道DC在正常肠粘膜中的炎症活性下调。因此，为了证实和扩展我们的初步结果，我们建议在这一应用中检验以下两个假设：(1)来自克罗恩病患者的原代人类肠道DC比来自正常肠道的DC更普遍、更成熟和更活跃，(2)与克罗恩病肠粘膜中的DC相比，正常肠粘膜中DC的成熟度和激活水平降低是由于肠道基质因子对DC从循环中招募到固有层。使用同源的原代肠道DC和M-DC，我们建议以以下两个具体目标来检验上述假设： 1.确定来自克罗恩病患者的小肠DC是否比来自正常肠道的DC更普遍、更成熟和更活跃，从而使来自克罗恩病组织的DC比来自正常肠道组织的DC更有效地提呈抗原。 2.确定正常肠粘膜DC较克罗恩病肠黏膜DC成熟和活化水平降低是否与肠道基质因子对DC的影响有关。

DESCRIPTION (provided by applicant): The regulation of macrophage and dendritic cell (DC) responses to ingested antigens and luminal microorganisms is a critical component of homeostasis in the intestinal muosa. We have reported that resident macrophages in normal human intestine are profoundly down-regulated for inflammatory responses due to exposure to mucosal stromal cell products, particularly TGF-beta (Smythies, et al. J. Clin. Invest. 115:66, '05). This down-regulation likely contributes to the near absence of inflammation in normal small intestine. Regarding intestinal DCs, our preliminary results suggest that resident DCs in normal human small intestinal mucosa are less prevalent, express lower levels of maturation and activation markers, and release lower levels of cytokines than DCs in the non-inflamed mucosa of patients with Crohn's disease. Thus, DCs in normal intestinal mucosa, like intestinal macrophages, may be down-regulated for inflammatory activity, suggesting that intestinal DCs also contribute to the low level of inflammation in normal intestinal mucosa, DCs in non-inflamed intestinal mucosa of patients with Crohn's disease may be less stringently downregulated and thus able to promote inflammation. Our preliminary results suggest that intestinal lamina propria stroma releases factors that down-regulate the maturity and inflammatory potential of monocyte-derived DCs (M-DCs), indicating a possible mechanism by which intestinal DCs, which likely are derived from the circulation, become down-regulated for inflammatory activity in normal intestinal mucosa. Therefore, to confirm and extend our preliminary results, we propose in this application to test the following two hypotheses: (1) Primary human intestinal DCs from patients with Crohn's disease are more prevalent, more mature and more activated than DCs from normal intestine and (2) The reduced level of maturity and activation of DCs in normal intestinal mucosa compared to that of DCs in Crohn's disease intestinal mucosa is due to intestinal stromal factors on DCs recruited from the circulation into the lamina propria. Using homologous primary intestinal DCs and M-DCs, we propose to test the above hypotheses with the following two Specific Aims: 1. Determine whether small intestinal DCs from patients with Crohn's disease are more prevalent, more mature and more activated than DCs from normal intestine, enabling DCs from Crohn's disease tissue to present antigen more efficiently than DCs from normal intestinal tissue. 2. Determine whether the reduced level of maturity and activation of DCs from normal intestinal mucosa compared to DCs from Crohn's disease mucosa is due to the effects of intestinal stromal factors on DCs.