IMMUNOREGULATORY DEFECTS IN INFLAMMATORY BOWEL DISEASE

指导我们研究炎症本质的工作假说 肠道疾病(IBD)是指这些疾病，特别是克罗恩病 疾病，是由于对无处不在的 粘膜抗原。近几年来，这一假说已经解决了。 对IBD患者T细胞免疫功能的研究 在各种条件下产生免疫调节性淋巴因子。在.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液(LP和PB T细胞， 分别)进行增殖并在以下情况下产生淋巴因子 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(具有几种不同的CD3和TCR 抗体)LP T细胞的增殖能力比外周血低10倍 另一方面，当通过CD2辅助途径刺激时， LP T细胞表现出更多的正常增殖反应(AS 与外周血T细胞相比)。这种无反应可能是一种形式的 外周T细胞无能，因为细胞功能部分恢复 通过将T细胞与IL-2预先孵育(在没有 TCR/CD3刺激)。与此形成鲜明对比的是 无反应“，LP T细胞表现出极大的增强能力 产生淋巴因子，包括IL-2、干扰素-γ和IL-4。在这方面， 而急性淋巴细胞白血病时，LP T细胞分泌的IL-2是BP T细胞的5-10倍 在刺激条件下，它们会分泌大量的IL-2(&gt；30,000 PG/M1/105细胞)。在可比的 IBD固有层T细胞的研究，几个重要的区别是 注意到了。首先，通过TCR/CD3途径诱导的应答是5- 比已经降低的对照LP T细胞反应低一倍， 通过旁路(CD2和CD28)诱导的反应被保留。 其次，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 (但不能分泌干扰素-γ)。第三，克隆氏病患者的T细胞 以类似方式刺激的患者表现为IL-2降低 分泌，但大大增加干扰素-γ和IL-4的分泌(5-10倍 增加)。因此这些研究定义了一种基本的淋巴因子分泌 与克罗恩病有关的缺陷。

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.