Role of TL1A in Severity of Crohn's Disease

TL1A 在克罗恩病严重程度中的作用

• 批准号: 9116825
• 负责人: Stephan R. Targan
• 金额: $ 36.32万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-15 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9116825
• 关键词: Affect; American; Animal Model; Antibodies; Biopsy; Cell physiology; Collagen; Colon; Complex; Crohn' s disease; Data; Deposition; Duodenum; Employee Strikes; Engineering; Environment; Fibroblasts; Fibrosis; Formalin; Gene Proteins; Genes; Genetic; Genetic Variation; Genotype; Grant; Haplotypes; Health; Human; Immune response; Immune system; In Vitro; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Interferons; Interleukin-13; Intestinal Fibrosis; Intestines; Investigation; Location; Lymphoid; Mediating; Modeling; Molecular; Molecular Profiling; Mucositis; Mus; Myelogenous; Myofibroblast; Operative Surgical Procedures; Organ; Pathogenesis; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Play; Predisposition; Refractory; Role; Sclerosing Cholangitis; Series; Severities; Severity of illness; Signal Transduction; Slide; Small Intestines; System; T-Lymphocyte; TNF gene; TNFSF15 gene; Testing; Therapeutic; Transcription Factor AP-1; Transgenic Mice; Ulcerative Colitis; Work; adaptive immunity; base; bile duct; cell type; clinical phenotype; cytokine; fibrogenesis; genome wide association study; human disease; ileum; in vivo; member; mouse model; neutralizing antibody; overexpression; patient population; prevent; programs; promoter; receptor; rectal; therapeutic target

DESCRIPTION (provided by applicant): Over the previous 2 cycles we contributed to the evidence that TNFSF15/TL1A is a pro-inflammatory gene/protein with influence over severity and with a role in a severe clinical phenotype seen in animal models and humans. We have shown in humans that TNFSF15 haplotypes are associated with increased/sustained expression of TL1A and aggressive Crohn's disease. To determine the in vivo consequences of elevated TL1A, we generated Tl1a transgenic mice (Tl1a Tg) with sustained lymphoid and/or myeloid Tl1a expression. Tl1a Tg spontaneously developed mild inflammation in the duodenum and ileum, with enhanced collagen deposition in small bowel and colon; which under colitogenic conditions, fulminated into discontinuous ileal and duodenal small bowel inflammation and fibrostenosis, as well as worsened proximal colonic inflammation. Tl1a Tg colitic mice developed primary ureteral strictures and obliteration of small bile ducts reminiscent of human sclerosing cholangitis. Tl1a antibody reduced inflammation and reversed fibrosis. Tl1a modulates the adaptive immune response by increasing pro-inflammatory factors including Ifn¿, Il13 and Il17. We generated mice with sustained lymphoid Tl1a expression but deficient in Ifn-¿, Il13 or Il17a and showed that Ifn-¿ deficiency enhanced, while Il17a-deficiency reduced inflammation and fibrosis, suggesting that Tl1a synergizes with other factors to modulate inflammation and fibrosis. To determine whether Tl1a can directly signal intestinal fibroblasts, we generated Dr3 deficient (Dr3-/-) mice and showed that Dr3, the only known receptor for Tl1a, is expressed on wild type (WT), but not Dr3-/- intestinal fibroblasts. Tl1a can increase collagen expression on WT but not Dr3-/- intestinal fibroblasts. Results from preliminary human studies are consistent with our findings in mice that TL1A modulates the severity and location of intestinal inflammation and fibrosis. CD patients with elevated TL1A expression require smaller bowel surgeries, have primary ureteral strictures, and have relative rectal sparing of inflammation. As seen in the mouse, our in vitro studies demonstrated direct TL1A induction of collagen expression from isolated human mucosal fibroblasts. Based on the work from our prior grant cycle and particularly the data supporting a role for TL1A in fibrosis leading to complicated clinical phenotypes in murine models and defined patient populations, we hypothesize that: TNFSF15/TL1A plays a central role in the induction and amplification of fibrosis by: 1) direct induction of fibroblast activation and differentiation into to myofibroblasts, which then express fibrosis-related factors; and 2) indirect induction of inflammatory cytokine programs, which independently activate fibrosis.

描述（由适用提供）：在前两个周期中，我们有助于证据表明TNFSF15/TL1A是一种促炎性基因/蛋白质，对严重程度有影响，并且在动物模型和人类中看到的严重临床表型中起作用。我们在人类中表明，TNFSF15单倍型与TL1A和侵略性克罗恩病的表达增加/持续表达有关。为了确定TL1A升高的体内后果，我们用持续的淋巴样和/或髓样TL1A表达产生了TL1A转基因小鼠（TL1A TG）。 TL1A TG在十二指肠和回肠自发发炎，在小肠和结肠中具有增强的胶原蛋白沉积。在Colitegen条件下，这完全进入了不连续的回肠和十二指肠小肠注射和纤维卵烯病，以及近端结肠感染的恶化。 TL1A TG colitic小鼠产生了原发性输尿管狭窄，小胆管的客观化使人想起人硬化的胆管炎。 TL1A抗体减少了炎症并逆转纤维化。 TL1A通过增加促炎性因素（包括IFN¿，IL13和IL17）来调节适应性免疫响应。我们产生了持续的淋巴样TL1A表达的小鼠，但缺乏IFN-€，IL13或IL17A，表明IFN-缺乏症增强了，而IL17A缺乏效率降低了注射和纤维化，这表明TL1A与其他因素协同调节注射和纤维化。为了确定TL1A是否可以直接信号信号肠成纤维细胞，我们产生了DR3缺乏（DR3 - / - ）小鼠，并表明DR3是唯一已知的TL1A受体，是在野生型（WT）上表达的，但未在DR3 - / - 肠道成骨成纤维成纤维基础上表达。 TL1A可以增加WT上的胶原蛋白表达，但不能增加DR3 - / - 肠成纤维细胞。初步研究的结果与我们在TL1A调节肠道感染和纤维化的严重程度和位置的小鼠中的发现一致。 TL1a表达升高的CD患者需要较小的肠道手术，具有原发性输尿管狭窄，并且具有相对直肠炎症的炎症。如小鼠中所见，我们的体外研究表明TL1A从分离的人粘膜成纤维细胞中直接诱导胶原蛋白表达。根据我们先前的赠款周期的工作，特别是支持TL1A在纤维化中角色的数据导致复杂的 在鼠模型和定义的患者人群中，我们假设：TNFSF15/TL1A在纤维化的诱导和扩增中起着核心作用：1）直接诱导成纤维细胞激活并分化为肌纤维，然后将其分化为肌纤维纤维化，然后将其当时表达的纤维化纤维化因素表现出来； 2）间接诱导炎症细胞因子程序，该程序独立激活纤维化。