Regulation Of Immune Responses In Humans And Non-human P

在先前的研究中，我们已经表明，在乙醇载体中直肠内给药恶沙酮会导致结肠炎的快速发展，其特征是溃疡、急性和慢性炎症细胞涌入肠道浅层和肠壁水肿。这张组织学图片更像溃疡性结肠炎（UC）而不是克罗恩病。事实上，两种结肠炎的细胞因子特征也有所不同：恶沙酮结肠炎是Th2结肠炎，其特征是IL-4和IL-5的高水平产生，而TNBS结肠炎是Th1结肠炎，其特征是IL-12和IFN-g的高水平产生。这些特征与对应人类疾病的细胞因子模式一致；因此，虽然UC与高IL-4水平无关，但与高IL-5水平相关，相反，CD与高IL-12和IFN-g水平相关。在一项关于恶沙酮结肠炎的新研究中，我们首先通过皮肤涂漆和直肠内低剂量接触物的预致敏，使小鼠产生了更持久的炎症；这使得对疾病进展进行更详细的研究成为可能。使用这种方法，我们发现IL-4产生的初始增加很快被IL-13的强烈反应所取代。此外，这种IL-13被证明是结肠炎的基本病理特征，因为后者可以通过给予IL-13抑制剂（IL-13Ra2-Fc）来预防。在进一步的研究中，我们发现恶沙酮结肠炎的发展取决于NK1.1+细胞的存在，因为用单克隆抗体预处理小鼠也可以阻止疾病的发展。然后，我们确定效应细胞实际上是NK-T细胞，因为：1)通过抗cd1抗体的施用来预防疾病；2) b2m缺陷小鼠、cd1缺陷小鼠和Ja281缺陷小鼠（即小鼠NK-T细胞反应的分子机制）均不能诱导疾病。在最后的一系列研究中，研究小组表明，实际上是NK-T细胞产生了IL-13。事实证明，用糖脂抗原（无乳糖神经酰胺）刺激结肠炎小鼠的细胞，仅在CD1背景下呈递给T细胞，仅刺激NK-T细胞，引起高IL-13反应。这些结果首次表明，NK-T细胞可以通过产生Th2细胞因子IL-13介导结肠炎。其意义在于溃疡性结肠炎可能是由类似的免疫机制引起的。

In previous studies we have shown that intra-rectal administration of oxazalone in an ethanol vehicle results in the rapid development of colitis characterized by ulceration, the influx of acute and chronic inflammatory cells in the superficial layer of the gut and bowel wall edema. This histologic picture was more like ulcerative colitis (UC) than Crohn?s disease (CD) and differed from the colitis induced by TNBS which resembles CD. Indeed, the cytokine profiles of the two colitides also differed: oxazalone colitis was a Th2 colitis marked by high level production of IL-4 and IL-5 whereas TNBS colitis was a Th1 colitis associated with high level production of IL-12 and IFN-g. These profiles were consistent with the cytokine patterns in the counterpart human diseases; thus, while UC is not associated with high IL-4 levels it is associated with high IL-5 levels and, in contrast, CD is associated with high IL-12 and IFN-g levels. In a new study of oxazalone colitis, we first developed a more longer lasting inflammation by pre-sensitizing the mice by skin painting and administering lower intra-rectal doses of contactant; this allowed a more detailed study of disease progression. Using this approach we showed that the initial increase in IL-4 production is rapidly superceded by a robust IL-13 response. Moreover, this IL-13 was shown to be an essential pathologic feature of the colitis as the latter could be prevented by administration of an IL-13 inhibitor (IL-13Ra2-Fc). In further studies we showed that the development of oxazalone colitis depends on the presence of an NK1.1+ cell since pre-treatment of mice with a monoclonal antibody also prevented disease development. We then determined that the effector cell was in fact a NK-T cell since: 1) disease was prevented by administration of anti-CD1 antibody; 2) disease could not be induced in b2m-deficient mice, CD1-deficient mice and Ja281 deficient mice, i.e., mice molecular machinery for NK-T cell responses. In a final series of studies, the research team showed that it was in fact the NK-T cells that were producing the IL-13. This was shown by the fact that stimulation of cells from mice with colitis with a glycolipid antigen (agalacosylceramide) that is only presented to T cells in the context of CD1 and only stimulates NK-T cells elicits a high IL-13 response. These results show for the first time that colitis can be mediated by NK-T cells producing a Th2 cytokine, IL-13. Their significance lies in the fact that ulcerative colitis may be caused by similar immunologic mechanisms.