Immunoregulatory Defects In Inflammatory Bowel Disease

在最初的研究中，我们建立了一个慢性胰腺炎模型，该模型是由反复剂量的低浓度蓝蛋白与FK56k5、NOD1配体联合引起的。与急性胰腺炎的胰腺相反，这种慢性疾病的胰腺纤维化和萎缩。重要的是，单独给药FK565或cerulein不会导致慢性胰腺炎，这表明这些药物协同作用诱导胰腺炎。在骨髓嵌合体的广泛研究中，我们确定慢性胰腺炎依赖于NOD1在非造血细胞（推测在腺泡细胞）中的表达，以及IFN-I在造血细胞和非造血细胞中的表达。在缺乏这些因素中的任何一个的情况下，一个人不会获得慢性胰腺炎表型和随之而来的纤维化。

In initial studies we established a chronic model of pancreatitis induced by repeated doses of low concentations of cerulein in combination with FK56k5, NOD1 ligand. In contrast to the pancreas in acute pancreatitis, the pancreas in this chronic disease was fibrotic and atrophied. Importantly, chronic pancreatitis was not achieved with administration of FK565 or cerulein alone, indicating that these agents act in synergy to induce the pancreatitis. In extensive studies of bone marrow chimeras we established that the chronic pancreatitis depends on the expression of NOD1 in non-hematopoietic cells (presumably in acinar cells) and on the expression of IFN-I in both hematopoietic cells and non-hematopoietic cells. In the absence of either of these factor one does not obtain the chronic pancreatitis phenotype and its attendant fibrosis. Extensive analysis of the cytokine profile of the inflamed pancreatitic tissue revealed the critical fact that the chronic pancreatitis was characterized by the secretion of IL-33, a cytokine usually produced in dying cells and giving rise to a Th2 cytokine profile via stimulation of the ST-2 receptor. In this case, however, a modified Th2 cytokine profile was observed in that IL-13 was produced but not IL-4; in addition, large amount of IFN-gamma and TNF-alpha were also produced. We speculate that this mixed, Th1/Th2 cytokine picture was due to the production of IFN-1 and its induction of IFN-gamma in various cell populations, particularly CD8+ cells. The IL-33 is most likely arising from damaged acinar cells that are further compromised by the release of TNF-alpha from inflammatory cells stimulated by IFN-I. Further studies disclosed the IL-33 induced secretion of IL-13 in conventional CD4+ T cells in that blockade of IL-13 greatly diminished fibrosis; thus the end-stage effector of fibrosis was IL-13. In summary, these studies lay bare the pathogenesis of chronic pancreatitis in a murine model that mimics the disease in humans. As such, these studies point to a number of possible ways in which chronic pancreatitis can be ameliorated, including the blockade of several of the inflammatory cytokines identified in the inflammatory process, IFN-I, IL-33 and IL-13. In addition, blockade of NOD1 signaling may also be a feasible treatment approach.