Immunoregulatory Defects In Inflammatory Bowel Disease

炎症性肠病的免疫调节缺陷

• 批准号: 9161441
• 负责人: Warren Strober
• 金额: $ 55.2万
• 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/9161441
• 关键词: Acinar Cell; Acute Disease; Address; Agonist; Atrophic; Bacteria; Bone Marrow; CCL2 gene; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cells; Chimera organism; Cholecystokinin Receptor; Chronic; Chronic Disease; Defect; Development; Disease; Dose; Fibrinogen; Fibrosis; Genetic Polymorphism; Goals; Hematopoietic; Human; Immunologic Factors; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Interferon Type II; Interferons; Interleukin-13; Interleukin-4; Intestines; Knowledge; Laboratories; Ligands; Modeling; Molecular; Molecular Analysis; Mus; NF-kappa B; Organ; Organism; Pancreas; Pancreatitis; Pathogenesis; Peptides; Phenotype; Population; Process; Production; Proteins; Role; STAT3 gene; Signal Transduction; Staging; Tissues; Tumor Necrosis Factor-alpha; acute pancreatitis; base; chemokine; chronic pancreatitis; cytokine; gut microflora; human TNF protein; interest; receptor; response; sensor

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.

在最初的研究中，我们建立了一种慢性胰腺炎模型，该模型是由重复剂量的低浓度雨蛙素联合FK56k5、NOD1配体诱导的。与急性胰腺炎的胰腺不同，这种慢性疾病的胰腺是纤维化和萎缩的。重要的是，单独使用FK565或雨蛙素不能实现慢性胰腺炎，这表明这些药物协同作用诱发了胰腺炎。在对骨髓嵌合体的广泛研究中，我们证实慢性胰腺炎依赖于非造血细胞(可能是腺泡细胞)中NOD1的表达，以及造血细胞和非造血细胞中干扰素-I的表达。如果没有这两个因素中的任何一个，就不会出现慢性胰腺炎的表型及其伴随的纤维化。 对炎症胰腺组织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是分泌IL-33，这是一种通常在濒死细胞中产生的细胞因子，通过刺激ST-2受体产生Th2细胞因子谱。然而，在这个病例中，观察到了修改的Th2细胞因子谱，产生了IL-13，但没有产生IL-4；此外，还产生了大量的干扰素-γ和肿瘤坏死因子-α。我们推测，这种混合的Th1/Th2细胞因子图像是由于在不同的细胞群，特别是CD8+细胞中产生了干扰素-1并诱导了干扰素-γ。IL-33很可能来自受损的腺泡细胞，在干扰素-I刺激的炎症细胞中释放肿瘤坏死因子-α，进一步损害了腺泡细胞的功能。进一步的研究揭示了IL-33可诱导传统的CD4+T细胞分泌IL-13，阻断IL-13可显著减轻纤维化，因此纤维化的终末效应因子为IL-13。 总而言之，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发现的几种炎性细胞因子，即干扰素-I、IL-33和IL-13。此外，阻断NOD1信号也可能是一种可行的治疗方法。