Regulation Of Immune Responses In Humans And Non-human P

人类和非人类免疫反应的调节

• 批准号: 6808163
• 负责人: WARREN 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/6808163
• 关键词: B lymphocyte; T cell receptor; T lymphocyte; cellular immunity; cytokine; cytotoxic T lymphocyte; enzyme linked immunosorbent assay; flow cytometry; helper T lymphocyte; human subject; immunomagnetic separation; immunoprecipitation; immunoregulation; interferon gamma; interleukin 10; interleukin 12; interleukin 13; interleukin 2; tissue /cell culture; transforming growth factors; ulcerative colitis; western blottings

While Crohn's disease (CD) has been clearly identified as a Th1-mediated inflammation, the immunopathogenesis of its counterpart inflammatory bowel disease, ulcerative colitis (UC), has remained enigmatic. In previous studies we developed an experimental mouse model of inflammation known as oxazolone colitis that bears a strong histopathologic resemblance to ulcerative colitis. In further work we established that the inflammation in oxazolone colitis is associated with an initial IL-4 response that rapidly gives way to an IL-13 response and that the latter arises from NKT cells, since it is elicited by a-galactosylceramide, a glycolipid antigen that stimulates "invariant chain" NKT cells when presented to the latter in association with CD1d. Finally, we showed that the IL-13-producing NKT cells are the cause of oxazolone colitis, since deletion of CD1d cells by anti-CD1d antibody or blockade of IL-13 by IL-13Ralpha2-Fc prevents the colitis. Similarly, disease could not be induced in knock-out mice lacking CD1d or components of the invariant TCR recognizing a-galactocylceramide. Taken together, these data indicated that an experimental inflammation resembling ulcerative colitis could be caused by an IL-13-secreting NKT cell. In a logical extension of these studies we show in the present work that lamina propria (LP) T cells from UC patients produce significantly greater amounts of IL-13 than control cells and little or no IFN-g, whereas comparable cells from CD patients produce large amounts of IFN-gamma and only small amounts of IL-13. In addition, we identified T cells bearing an NK marker as the source of the IL-13, but showed that these cells were not NKT cells bearing an invariant TCR since they were not stained by a-galactocylceramide-loaded CD1d tetramers and could not be stimulated to produce IL-13 by a-galactocylceramide. Nevertherless, their designation as NKT cells (with non-invariant TCR?s) was assured by their ability to produce IL-13 following stimulation by a B cell transfected with high levels of CD1d. These studies indicate that UC is associated with an atypical Th2 response characterized by IL-13-producing non-invariant NKT cells. That this response is pathologic is strongly suggested by the prior studies of oxazolone colitis (described above) showing that NKT cells producing IL-13 is the cause of experimental colitis resembling UC. Overall, these studies clear the way to treatment of patients with ulcerative colitis with agents that block the IL-13 response.

虽然克罗恩病（CD）已清楚地识别为Th1介导的炎症，但其对应炎症性肠病，溃疡性结肠炎（UC）的免疫发作仍然是神秘的。在先前的研究中，我们开发了一种被称为恶唑酮结肠炎的炎症的实验小鼠模型，该模型与溃疡性结肠炎具有很强的组织病理学相似之处。 In further work we established that the inflammation in oxazolone colitis is associated with an initial IL-4 response that rapidly gives way to an IL-13 response and that the latter arises from NKT cells, since it is elicited by a-galactosylceramide, a glycolipid antigen that stimulates "invariant chain" NKT cells when presented to the latter in association with CD1d.最后，我们表明产生IL-13的NKT细胞是恶唑酮结肠炎的原因，因为抗CD1D抗体通过IL-13ralpha2-FC抑制了CD1D细胞IL-13，可预防结肠炎。同样，在缺乏CD1D的敲除小鼠或不变的TCR识别A-半乳糖基酰胺的成分的敲除小鼠中也无法诱发疾病。综上所述，这些数据表明，类似于溃疡性结肠炎的实验性炎症可能是由分泌IL-13的NKT细胞引起的。 在这些研究的逻辑扩展中，我们在本工作中表明，来自UC患者的固有层（LP）T细胞产生的IL-13量明显大于对照细胞，而少于或没有IFN-G，而CD患者的可比较细胞产生了大量IFN-GAMMA，只有少量的IL-13。此外，我们确定了带有NK标记物为IL-13来源的T细胞，但表明这些细胞不是带有不变TCR的NKT细胞，因为它们未被A-半乳糖酰胺的CD1D Tetramer染色，并且无法刺激A-Galactocylcylceramide刺激IL-13。从未没有任何无动不动的人称其为NKT细胞（具有非不变的TCR？s），可以通过用高水平CD1D转染的B细胞刺激后产生IL-13的能力。这些研究表明，UC与以IL-13产生非不变的NKT细胞为特征的非典型TH2反应有关。先前对恶唑酮结肠炎（上述）的研究表明，这种反应是病理性的，表明产生IL-13的NKT细胞是类似于UC的实验性结肠炎的原因。总体而言，这些研究清除了用阻断IL-13反应的药物治疗溃疡性结肠炎患者的方法。