IMMUNOREGULATORY DEFECTS IN INFLAMMATORY BOWEL DISEASE

指导我们研究炎症本质的工作假设 肠道疾病（IBD）是这些疾病，特别是克罗恩病， 疾病，是由于对无处不在的 粘膜抗原 近年来，这一假设已经解决了 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 目前，我们首先定义了控制T细胞的能力， 来源于固有层和外周血（LP和PB T细胞， 分别）进行增殖和产生淋巴因子， 通过确定的T细胞活化途径刺激。 我们发现，当 通过TCR/CD 3途径（用几种不同的CD 3和TCR LPT细胞表现出比PB低10倍的增殖 细胞;另一方面，当通过CD 2辅助途径刺激时， LP T细胞表现出相当多的正常增殖反应（如 与PB T细胞相比）。 这种无反应可能是一种形式的 外周T细胞无反应性，因为部分恢复细胞功能， 通过将T细胞与IL-2预孵育（在不存在IL-2的情况下）获得。 TCR/CD 3刺激）。 与此相反的是，这种“增殖” “无反应性”，LP T细胞表现出极大提高的能力， 产生淋巴因子，包括IL-2、IFN-γ和IL-4。 在这方面，委员会注意到， 而LP T细胞分泌的IL-2是BP T细胞的5-10倍， 在刺激条件下，它们分泌显著量的IL-2（> 30，000 pg/m1/105细胞）。 按可比 IBD固有层T细胞的研究中，几个重要的差异是 知道了 首先，虽然通过TCR/CD 3途径诱导的应答是5- 比已经降低的对照LP T细胞应答低1倍， 保留了通过辅助途径（CD 2和CD 28）诱导的应答。 其次，来自溃疡性结肠炎患者的T细胞，通过 旁路，表现为IL-2和IL-4分泌略有减少 (but而不是IFN-γ分泌）。 第三，克罗恩病的T细胞 以类似方式刺激的患者表现出IL-2降低， 分泌，但IFN-γ和IL-4分泌大大增加（5-10倍 增加）。 因此，这些研究确定了一种基本的淋巴因子分泌 与克罗恩病相关的缺陷。

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.