IMMUNOREGULATORY DEFECTS IN INFLAMMATORY BOWEL DISEASE

炎症性肠病的免疫调节缺陷

• 批准号: 5200452
• 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/5200452
• 关键词: CD antigens; T cell receptor; T lymphocyte; anergy; cytokine; human subject; immunopathology; immunoregulation; inflammatory bowel diseases; interferon gamma; interleukin 2; interleukin 4; intestinal mucosa; leukocyte activation /transformation; lymphocyte proliferation; mucosal immunity; receptor expression; tissue /cell culture

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 plus minus 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 unrespon-siveness was a form of reversible anergy. In 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 amounts 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 crosslinked 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.

炎症性肠病（IBD）的研究表明， 异常包括不受限制的免疫反应，而不是 新抗原，而是粘膜系统所针对的共同抗原， 通常没有反应。 为了收集与这个假设相关的数据 我们对对照固有层T细胞进行了广泛的研究。 在最初的研究中，我们确定，与对照外周血相比， 血液T细胞，固有层T细胞表现出大大降低的反应 通过TCR/CD 3途径刺激。 这是真的当细胞 作为相对未纯化的形式进行研究，或者当作为高度纯化的形式进行检查时， 纯化的CD 4 + T细胞。 通过替代途径的反应，即，通过CD 2 +-CD 28也减少，但不像通过 TCR/CD3。 此外，无响应状态可以至少部分地 在单独的IL-2中培养的细胞逆转（不 IL-2加增殖刺激）24小时;这表明， 反应迟钝是一种可逆的无反应性。 在进一步的研究中， 我们检测了外周血和固有层T细胞的能力， 在上述刺激条件下产生各种细胞因子。 我们发现外周血和固有层T细胞 产生相对少量的IL-2，以及IFN-γ或IL-4，当 单独通过TCR/CD 3途径刺激，但当 通过CD 2/CD 28共刺激途径刺激。 所以尽管 固有层T细胞表现出大大降低的增殖的事实， 与外周血相比， T细胞。 最后，我们进行了研究，以阐明机制， 这种“分裂”的无反应性。 特别是，我们交联了 TCR/CD 3 T细胞在严格的条件下，并确实诱导T细胞 无反应性（通过TCR/CD 3途径对后续刺激）。 然而，这些细胞也不再通过CD 2途径应答 通过增殖或细胞因子产生。 因此 固有层细胞的无反应性/反应性还不能被 在文化中复制。 总的来说，这些研究表明， T细胞达到一种独特的功能状态，使它们能够充当 局部粘膜环境中的效应细胞。