IMMUNOREGULATORY DEFECTS IN INFLAMMATORY BOWEL DISEASE

对炎症性肠病(IBD)的研究表明， 异常包括一种不受约束的免疫反应，而不是对新奇的 抗原，而不是针对粘膜系统所针对的共同抗原 通常反应迟钝。为了收集与这一假设相关的数据，我们 对控制固有层T细胞进行了广泛的研究。在……里面 初步研究表明，与对照外周相比， 血T细胞、固有层T细胞反应显著减弱 通过TCR/CD3途径进行刺激。这是正确的当细胞 作为一种相对不纯净的形式被研究，或者当被高度检查时 纯化的CD4+T细胞。通过其他途径的反应，即通过CD2 +/-CD28也降低，但不像TCR/CD3那样降低。在……里面 此外，无响应状态至少可以通过以下方式部分逆转 单独使用IL-2(不含IL-2+增殖刺激)培养细胞24天 小时；这表明无反应是一种可逆的 无能。在进一步的研究中，我们检测了外周血的容量 和固有层T细胞在上述情况下产生各种细胞因子 刺激条件。在这里我们发现外周血和 固有层T细胞产生相对较少的IL-2，以及 当仅通过TCR/CD3途径刺激时，干扰素-γ或IL-4，但 通过CD2/CD28共刺激产生大量 路径。因此，尽管固有层T细胞表现出 极大地减少了增殖，它们产生的细胞因子与 与外周血T细胞相比。最后，我们进行了研究，以 解释这种形式的“分裂”无反应的机制。在……里面 特别是，我们在严格的条件下使TCR/CD3 T细胞交联化 确实导致T细胞无反应(对随后的刺激通过 TCR/CD3途径)。然而，这样的细胞也不再有反应 通过CD2途径增殖或产生细胞因子。因此， 固有层细胞的无反应性/反应性还不能 在培养中繁殖。总体而言，这些研究揭示了固有层 T细胞达到一种独特的功能状态，这使它们能够发挥作用 局部粘膜环境中的效应细胞。

Studies of inflammatory bowel disease (IBD) suggest that the basic abnormality consists of an unrestrained immunologic response, not to novel antigen, but rather to common antigens to which the mucosal system is ordinarily unresponsive. To gather data relevant to this hypothesis we have performed extensive studies of control lamina propria T cells. In initial studies we established that as compared to control peripheral blood T cells, lamina propria T cells manifest a greatly reduced response to stimulation via the TCR/CD3 pathway. This was true when cells were studied as a relatively unpurified form or when examined as highly purified CD4+ T cells. Responses via alternative pathways, i.e., via CD2 +/- CD28 were also reduced, but not nearly so reduced as via TCR/CD3. In addition, the unresponsive state could be at least partially reversed by cultured cells in IL-2 alone (not IL-2 plus proliferative stimulus) for 24 hours; this suggested that the unresponsiveness was a form of reversible anergy. Tn further studies, we examined the capacity of peripheral blood and lamina propria T cells to produce various cytokines under the above stimulation conditions. Here we found that both peripheral blood and lamina propria T cells produced relatively low amount of IL-2, as well as IFN-gamma or Il-4, when stimulated via the TCR/CD3 pathway alone, but produced large amounts when stimulated via the CD2/CD28 co-stimulatory pathway. Thus, despite the fact that lamina propria T cells manifest greatly reduced proliferation, they produce as much or more cytokines, as compared to peripheral blood T cells. Finally, we performed studies to elucidate the mechanism of this form of "split" unresponsiveness. In particular, we cross-linked TCR/CD3 T cells under stringent conditions and did indeed induce T cell unresponsiveness (to subsequent stimulation via the TCR/CD3 pathway). However, such cells were also no longer responsive via the CD2 pathway either by proliferation or cytokine production. Thus, the unresponsiveness/responsiveness of lamina propria cells cannot yet be reproduced in culture. Overall, these studies reveal that lamina propria T cells achieve a unique functional state which allows them to act as effector cells in the local mucosal environment.