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: 7023429
• 负责人: LESLEY E SMYTHIES
• 金额: $ 18.19万
• 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 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7023429
• 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（由申请方提供）：巨噬细胞和树突状细胞（DC）对摄入抗原和管腔微生物应答的调节是肠粘膜内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，正常人肠中的常驻巨噬细胞对于炎症反应被显著下调（Smythies等人，J.Clin.Invest.2005，2006）。115：66，'05）。这种下调可能有助于正常小肠中几乎没有炎症。关于肠道树突状细胞，我们的初步结果表明，居民在正常人小肠粘膜的树突状细胞是不太普遍，表达较低水平的成熟和活化标志物，并释放较低水平的细胞因子比在克罗恩病患者的非炎症粘膜的树突状细胞。因此，正常肠粘膜中的DC，像肠巨噬细胞一样，可以下调炎症活性，表明肠DC也有助于正常肠粘膜中的低水平炎症，克罗恩病患者的非炎症肠粘膜中的DC可能不太严格地下调，因此能够促进炎症。我们的初步研究结果表明，肠固有层基质释放因子，下调单核细胞衍生的DC（M-DC）的成熟和炎症潜力，表明一种可能的机制，肠道DC，这可能是来自循环，成为下调正常肠粘膜的炎症活动。因此，为了证实和扩展我们的初步结果，我们在本申请中提出测试以下两个假设：（1）来自克罗恩病患者的原代人肠DC更普遍，比来自正常肠的DC更成熟和更活化，和（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肠基质因子对从循环募集到固有层的DC的影响。使用同源原代肠道DC和M-DC，我们提出用以下两个特定目的来检验上述假设： 1.确定来自克罗恩病患者的小肠DC是否比来自正常肠的DC更普遍、更成熟和更活化，使来自克罗恩病组织的DC比来自正常肠组织的DC更有效地呈递抗原。 2.确定与克罗恩病粘膜的DC相比，正常肠粘膜的DC成熟和活化水平降低是否是由于肠基质因子对DC的影响。