IMMUNOREGULATORY DEFECTS IN INFLAMMATORY BOWEL DISEASE

炎症性肠病的免疫调节缺陷

• 批准号: 3768779
• 负责人: W STROBER
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3768779
• 关键词: Crohn's disease; T cell receptor; T lymphocyte; anergy; human subject; immunopathology; immunoregulation; inflammatory bowel diseases; interferon gamma; interleukin 2; interleukin 4; intestinal mucosa; leukocyte activation /transformation; lymphocyte proliferation; lymphokines; receptor expression; ulcerative colitis

The working hypothesis guiding our research on the nature of inflammatory bowel diseases (IBD) is that these diseases, particularly Crohn's disease, are due to abnormal regulation of responses to ubiquitous mucosal antigens. In recent years, this hypothesis has resolved itself into studies on the ability of T cells obtained from IBD patients to produce immunoregulatory lymphokines under various conditions. During the current period we have first defined the capacity of control T cells derived from lamina propria and the peripheral blood (LP and PB T cells, respectively) to undergo proliferation and to produce lymphokines when stimulated via defined T cell activation pathways. We found that when stimulated via the TCR/CD3 pathway (with several different CD3 and TCR antibodies) LP T cells exhibited 10-fold less proliferation than PB cells; on the other hand, when stimulated via the CD2 accessory pathway, LP T cells exhibited considerably more normal proliferative responses (as compared to PB T cells). This non-responsiveness was probably a form of peripheral T cell anergy, since partial recovery of cell function was obtained by pre-incubation of T cells with IL-2 (in the absence of TCR/CD3 stimulation). In contrast to this "proliferative unresponsiveness", LP T cells exhibit a greatly heightened capacity to produce lymphokines, including IL-2, IFN-gamma and IL-4. In this regard, while LP T cells secreted 5-10-fold more IL-2 than BP T cells under all stimulatory conditions, they secreted remarkable amounts of IL-2 (>30,000 pg/m1/105 cells) when stimulated via accessory pathways. In comparable studies of IBD lamina propria T cells, several important differences were noted. Firstly, while responses induced via the TCR/CD3 pathway were 5- fold lower than the already reduced control LP T cell responses, responses induced via accessory pathways (CD2 and CD28) were preserved. Secondly, T cells from ulcerative colitis patients, stimulated via accessory pathways, manifested somewhat reduced IL-2 and IL-4 secretion (but not IFN-gamma secretion). Thirdly, T cells from Crohn's disease patients stimulated in a similar fashion manifested reduced IL-2 secretion, but vastly increased IFN-gamma and IL-4 secretion (5-10-fold increases). These studies therefore define a basic lymphokine secretory defect associated with Crohn's disease.

指导我们研究炎症本质的工作假设 肠道疾病 (IBD) 是指这些疾病，特别是克罗恩病 疾病，是由于对普遍存在的反应的异常调节造成的 粘膜抗原。 近年来，这个假说已经得到解决 研究从 IBD 患者获得的 T 细胞的能力 在各种条件下产生免疫调节淋巴因子。 期间 本期我们首先定义了控制T细胞的能力 源自固有层和外周血（LP 和 PB T 细胞， 分别）进行增殖并产生淋巴因子 通过确定的 T 细胞激活途径进行刺激。 我们发现当 通过TCR/CD3途径刺激（有几种不同的CD3和TCR 抗体）LP T 细胞的增殖能力比 PB 低 10 倍 细胞；另一方面，当通过 CD2 旁路途径刺激时， LP T 细胞表现出明显更正常的增殖反应（如 与 PB T 细胞相比）。 这种无反应可能是一种形式 外周 T 细胞无反应，因为细胞功能部分恢复 通过将 T 细胞与 IL-2 预孵育获得（在没有 TCR/CD3 刺激）。 与这种“增殖 无反应性”，LP T 细胞表现出极大增强的能力 产生淋巴因子，包括 IL-2、IFN-γ 和 IL-4。 对此， 而LP T细胞在所有条件下分泌的IL-2比BP T细胞多5-10倍 在刺激条件下，它们分泌大量的 IL-2（>30,000 pg/m1/105 细胞）通过旁路刺激时。 在可比的 IBD 固有层 T 细胞的研究，几个重要的差异是 著名的。 首先，虽然通过 TCR/CD3 途径诱导的反应是 5- 比已经降低的对照 LP T 细胞反应低几倍， 通过旁路（CD2 和 CD28）诱导的反应被保留。 其次，来自溃疡性结肠炎患者的 T 细胞，通过刺激 旁路，表现为 IL-2 和 IL-4 分泌有所减少 （但不分泌 IFN-γ）。 第三，来自克罗恩病的T细胞 以类似方式刺激的患者表现出 IL-2 减少 分泌，但大大增加了 IFN-γ 和 IL-4 的分泌（5-10 倍） 增加）。 因此，这些研究定义了基本的淋巴因子分泌 与克罗恩病相关的缺陷。