Understanding lipid antigen presentation in intestinal homeostasis and inflammation

了解肠道稳态和炎症中的脂质抗原呈递

• 批准号: MR/L008157/1
• 负责人: Patricia Barral
• 金额: $ 61.79万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FL008157%2F1
• 关键词: Understanding; lipid; antigen; presentation; intestinal

Humans carry around 10 times more microorganisms in the intestine as total cells constituting our body. These microorganisms (predominantly bacteria) perform many important metabolic functions for example helping in the digestion of the food to allow the absorption of nutrients. However, to prevent uncontrolled overgrowth and dissemination of intestinal bacteria the human body had developed a great variety of strategies that allow bacterial containment within the intestine. As such, the human gastrointestinal tract houses the big bulk of the immune system, and many different cell types cooperate to maintain a healthy relationship with our gut flora. Importantly, alteration of this equilibrium can lead to the development of intestinal disorders like is the case of Inflammatory Bowel Disease (IBD) that affects 1 in 250 people in the UK. IBD comprises a mixture of life-long disorders that may be ameliorated with immunosuppressive drugs but not cured, with around 40% of patients being considered for surgery normally involving removal of the affected bowel. Added to this, IBD patients show up to 18% increased risk of colorectal cancer over 30 years post disease onset. Therefore understanding the factors that modulate the cross-talk between the intestinal flora and the immune cells is critical to identify new therapeutic targets for the treatment of intestinal diseases. This proposal centers on the understanding of the role of a population of immune cells, so called NKT cells, within the intestine, both in healthy conditions and during the development of IBD. NKT cells are known to be present in the gastrointestinal tract and they have been proposed to function in the containment of intestinal bacteria. In addition to this, NKT cells accumulate in the intestine of IBD patients where they may play a role in the initiation of the disease. However the mechanisms that regulate the activation of these cells and their role in the development of IBD remain unclear. We aim to deliver fundamental new insights into the mechanisms regulating NKT cell function within the intestine with the ultimate goal of manipulating this knowledge in our advantage to design new treatments for intestinal disorders.

人类肠道中携带的微生物大约是构成我们身体的细胞总数的10倍。这些微生物(主要是细菌)执行许多重要的新陈代谢功能，例如帮助消化食物以吸收营养。然而，为了防止肠道细菌不受控制地过度生长和传播，人体开发了各种策略，允许细菌在肠道内受到遏制。因此，人类胃肠道容纳了免疫系统的大部分，许多不同类型的细胞相互合作，与我们的肠道菌群保持健康的关系。重要的是，这种平衡的改变会导致肠道疾病的发展，比如炎症性肠病(IBD)，在英国每250人中就有1人受到影响。IBD包括一种终生疾病的混合物，这些疾病可以通过免疫抑制药物改善，但无法治愈，大约40%的患者被考虑进行手术，通常涉及切除受影响的肠道。此外，IBD患者在发病后30年内患结直肠癌的风险增加了18%。因此，了解调节肠道菌群和免疫细胞之间的串扰的因素对于确定肠道疾病治疗的新靶点至关重要。这一建议的核心是理解一群免疫细胞，即所谓的NKT细胞，在健康条件下和IBD发展过程中在肠道中所起的作用。已知NKT细胞存在于胃肠道中，它们被认为具有抑制肠道细菌的功能。除此之外，NKT细胞在IBD患者的肠道中积聚，在疾病的启动过程中可能发挥作用。然而，调控这些细胞激活的机制及其在IBD发展中的作用仍不清楚。我们的目标是对肠道内NKT细胞功能的调节机制提供根本的新见解，最终目标是利用这些知识为我们的优势设计新的肠道疾病治疗方法。

项目成果

Correction: Tissue-specific shaping of the TCR repertoire and antigen specificity of iNKT cells.

修正：TCR 库的组织特异性塑造和 iNKT 细胞的抗原特异性。

• DOI: 10.7554/elife.56997
• 发表时间: 2020
• 期刊: eLife
• 影响因子: 7.7
• 作者: Jimeno R

CD1d-mediated activation of group 3 innate lymphoid cells drives IL-22 production.

• DOI: 10.15252/embr.201642412
• 发表时间: 2017-01
• 期刊: EMBO reports
• 影响因子: 7.7
• 作者: Saez de Guinoa J;Jimeno R;Farhadi N;Jervis PJ;Cox LR;Besra GS;Barral P
• 通讯作者: Barral P