Immunoregulatory Defects In Inflammatory Bowel Disease

在前期研究中，我们建立了低浓度雨蛙肽与FK 56 k5、NOD 1配体联合重复给药诱导的慢性胰腺炎模型。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，单独给予FK 565或雨蛙肽不会导致慢性胰腺炎，表明这些药物协同作用诱导胰腺炎。在对骨髓嵌合体的广泛研究中，我们确定慢性胰腺炎依赖于NOD 1在非造血细胞（可能是腺泡细胞）中的表达以及IFN-1在造血细胞和非造血细胞中的表达。在缺乏这些因子的情况下，不会获得慢性胰腺炎表型及其伴随的纤维化。 对发炎胰腺炎组织的细胞因子谱的广泛分析揭示了一个关键事实，即慢性胰腺炎的特征在于IL-33的分泌，IL-33是一种细胞因子，通常在垂死细胞中产生，并通过刺激ST-2受体产生Th 2细胞因子谱。 然而，在这种情况下，观察到修饰的Th 2细胞因子谱，其中产生IL-13但不产生IL-4;此外，还产生大量IFN-γ和TNF-α。 我们推测，这种混合的Th 1/Th 2细胞因子图片是由于IFN-1的产生及其在各种细胞群，特别是CD 8+细胞中对IFN-γ的诱导。 IL-33最有可能是由受损的腺泡细胞引起的，这些腺泡细胞被IFN-1刺激的炎性细胞释放的TNF-α进一步损害。进一步的研究公开了IL-33诱导的IL-13在常规CD 4 + T细胞中的分泌，因为IL-13的阻断大大减少了纤维化;因此纤维化的终末期效应物是IL-13。 总之，这些研究揭示了慢性胰腺炎在模拟人类疾病的小鼠模型中的发病机制。 因此，这些研究指出了许多可以改善慢性胰腺炎的可能方法，包括阻断炎症过程中鉴定的几种炎性细胞因子IFN-I、IL-33和IL-13。 此外，阻断NOD 1信号传导也可能是一种可行的治疗方法。

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.