Regulation Of Immune Responses In Humans And Non-human P

虽然克罗恩病（CD）已被明确确定为Th 1介导的炎症，但其对应的炎症性肠病溃疡性结肠炎（UC）的免疫发病机制仍然是个谜。在以前的研究中，我们开发了一种称为恶唑酮结肠炎的实验小鼠炎症模型，其与溃疡性结肠炎具有很强的组织病理学相似性。在进一步的工作中，我们确定恶唑酮结肠炎的炎症与初始IL-4应答相关，该应答迅速让位于IL-13应答，并且后者由NKT细胞引起，因为它是由α-半乳糖神经酰胺引起的，α-半乳糖神经酰胺是一种糖脂抗原，当与CD 1d一起呈递给NKT细胞时，刺激“不变链”NKT细胞。最后，我们发现产生IL-13的NKT细胞是恶唑酮结肠炎的原因，因为抗CD 1d抗体缺失CD 1d细胞或IL-13 Ra 2-Fc阻断IL-13可预防结肠炎。类似地，在缺乏CD 1d或识别α-半乳糖神经酰胺的不变TCR的组分的敲除小鼠中不能诱导疾病。总之，这些数据表明，类似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。 在这些研究的逻辑延伸中，我们在目前的工作中表明，UC患者的固有层（LP）T细胞产生的IL-13的量显著高于对照细胞和很少或没有IFN-γ，而CD患者的可比细胞产生大量的IFN-γ和仅少量的IL-13。此外，我们鉴定了携带NK标志物的T细胞作为IL-13的来源，但表明这些细胞不是携带不变TCR的NKT细胞，因为它们不被α-半乳糖神经酰胺负载的CD 1d四聚体染色，并且不能被α-半乳糖神经酰胺刺激产生IL-13。尽管如此，它们被称为NKT细胞（具有非恒定TCR？s）是通过它们在用高水平CD 1d转染的B细胞刺激后产生IL-13的能力来保证的。这些研究表明，UC与以产生IL-13的非恒定NKT细胞为特征的非典型Th 2应答相关。先前的恶唑酮结肠炎研究（如上所述）强烈表明这种反应是病理性的，表明产生IL-13的NKT细胞是类似UC的实验性结肠炎的原因。总的来说，这些研究为用阻断IL-13反应的药物治疗溃疡性结肠炎患者扫清了道路。

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.