Immunobiology of Dendritic Cells in Crohn's Disease

克罗恩病树突状细胞的免疫生物学

• 批准号: 7140648
• 负责人: LESLEY E SMYTHIES
• 金额: $ 17.76万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-30 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7140648
• 关键词: Crohn' s disease; antigen presentation; cell biology; cell differentiation; clinical research; dendritic cells; flow cytometry; human subject; immune response; immunocytochemistry; immunoregulation; inflammation; intestinal mucosa; mass spectrometry; phagocytosis; phenotype; receptor expression; stromal cells; transforming growth factors

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.

描述（由申请人提供）：巨噬细胞和树突细胞（DC）对摄入的抗原和管腔微生物的反应的调节是肠粘膜稳态的关键组成部分。我们已经报道，由于暴露于粘膜基质细胞产物，特别是 TGF-β，正常人肠道中的常驻巨噬细胞的炎症反应被深度下调（Smythies 等人 J. Clin. Invest. 115:66, '05）。这种下调可能导致正常小肠几乎不存在炎症。关于肠道 DC，我们的初步结果表明，与克罗恩病患者非炎症粘膜中的 DC 相比，正常人小肠粘膜中的常驻 DC 较少普遍，表达较低水平的成熟和激活标记物，并释放较低水平的细胞因子。因此，正常肠粘膜中的DC与肠道巨噬细胞一样，可能因炎症活性而下调，这表明肠道DC也有助于正常肠粘膜的低水平炎症，而克罗恩病患者的非炎症肠粘膜中的DC可能下调程度不那么严格，因此能够促进炎症。我们的初步结果表明，肠固有层基质释放下调单核细胞来源的 DC (M-DC) 成熟度和炎症潜力的因子，这表明可能源自循环系统的肠道 DC 在正常肠粘膜中炎症活性下调的可能机制。因此，为了证实和扩展我们的初步结果，我们在本申请中建议测试以下两个假设：(1)来自克罗恩病患者的原代人肠道DC比来自正常肠道的DC更普遍、更成熟和更活化，以及(2)与克罗恩病肠粘膜中的DC相比，正常肠粘膜中的DC的成熟和活化水平降低。 是由于 DC 上的肠基质因子从循环系统募集到固有层所致。使用同源的原代肠道 DC 和 M-DC，我们建议通过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 能够比来自正常肠道组织的 DC 更有效地呈递抗原。 2.确定与来自克罗恩病粘膜的DC相比，来自正常肠粘膜的DC的成熟度和活化水平降低是否是由于肠基质因子对DC的影响。