Targeting New Mechanisms In The Control Of Thymus Function To Restore Balanced T-cell Production

针对胸腺功能控制的新机制恢复 T 细胞生成的平衡

• 批准号: MR/T029765/1
• 负责人: Graham Anderson
• 金额: $ 236.19万
• 依托单位: University of Birmingham
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FT029765%2F1
• 关键词: Targeting; New; Mechanisms; Control; Thymus

The immune system is a mixture of cells and tissues in our body that has multiple essential functions. First, immune cells fight infection by viruses, bacteria and parasites, which are collectively called pathogens. Indeed, as scientists we have hijacked this remarkable ability of the immune system to identify and target foreign invaders by creating the process of immunization, where harmless forms of pathogens can be used as vaccines that then protect us from potentially life threatening diseases. Second, our immune systems are important in recognizing and mounting responses to tumours that form during cancer. Most recently, effective therapies for cancer treatment use approaches to boost the ability of immune cells to recognize and target cancers, which again highlights the importance of the immune system in health and disease. For all aspects of immune system function, T-cells are considered as essential orchestra conductors. T-cells are a specialized type of white blood cell with multiple functions. For example, they can can either directly kill pathogens, or help other immune cells to function. Importantly, T-cells are only made in one site in the body, an organ called the thymus. This organ lies above the heart in the chest, and its sole purpose is to support the complex process of T-cell development. As such, understanding how the thymus works is fundamentally important in understanding how our immune systems work. Without a functional thymus, the immune system is severely compromised, and we are left vulnerable to pathogens that would otherwise be innocuous. Despite the known importance of the thymus, we still do not understand how the thymus develops and functions. This limitation is a major bottleneck in being able to manipulate the immune system to generate better treatments for diseases where T-cell development is absent or reduced (immunodeficiency) or targeted against our own body (autoimmunity). In addition, as the thymus gets smaller with age, the immune system in elderly life becomes compromised. This provides multiple major obstacles. First, it limits the success of vaccination in the elderly. Second, it impacts upon the successful use of bone marrow transplantation for cancer patients, where recovery of normal immune function depends on a functional thymus. We believe that by understanding the thymus, we will be able to limit life-threatening diseases, and improve the treatment of cancer. We know that epithelial cells present in the thymus are important for its function, but we don't know how these cells work. By identifying new types of epithelial cell, we will work out which parts of the thymus are responsible for its function. In addition, by discovering how the thymus produces different types of T-cell, in both health and following bone marrow transplant, we will be able to manipulate and monitor thymus function. Through the identification of mechanisms that control the thymus in health, we will be able to identify new targets to boost thymus function in disease. Ultimately, our research will mean that we will have a far deeper understanding of the way in which an essential organ works in our immune systems, which we can then use to design better, more effective and specific therapies that correct or improve multiple immune disorders.

免疫系统是我们体内具有多个基本功能的细胞和组织的混合物。首先，免疫细胞与病毒，细菌和寄生虫的感染作斗争，这些病毒被称为病原体。的确，作为科学家，我们劫持了免疫系统通过创造免疫进程来识别和瞄准外国入侵者的非凡能力，在这种情况下，无害的病原体形式可以用作疫苗，然后保护我们免受潜在的威胁生命危害生命的疾病。其次，我们的免疫系统在识别和对癌症过程中形成的肿瘤的反应中很重要。最近，用于癌症治疗方法的有效疗法可以提高免疫细胞识别和靶向癌症的能力，这再次强调了免疫系统在健康和疾病中的重要性。对于免疫系统功能的所有方面，T细胞被认为是必需的乐团导体。 T细胞是具有多种功能的专用白细胞。例如，它们可以直接杀死病原体，也可以帮助其他免疫细胞发挥作用。重要的是，T细胞仅在体内的一个部位中制成，一种称为胸腺的器官。该器官位于胸部的心脏上方，其唯一目的是支持T细胞发育的复杂过程。因此，了解胸腺的工作原理对于理解我们的免疫系统的工作原理至关重要。没有功能性胸腺，免疫系统将严重损害，我们容易受到原本无害的病原体的影响。尽管百里香是已知的重要性，但我们仍然不了解胸腺的发展和功能。这种限制是能够操纵免疫系统的主要瓶颈，以便为缺乏或降低T细胞发育的疾病产生更好的治疗方法（免疫缺陷）或针对我们自己的身体（自身免疫性）。此外，随着胸腺随着年龄的增长而变小，老年人生活中的免疫系统也会受到损害。这提供了多个主要障碍。首先，它限制了老年人疫苗接种的成功。其次，这会影响癌症患者的骨髓移植成功使用，在这种情况下，正常免疫功能取决于功能性胸腺。我们认为，通过了解百里香，我们将能够限制威胁生命的疾病并改善癌症的治疗方法。我们知道，胸腺中存在的上皮细胞对其功能很重要，但我们不知道这些细胞如何工作。通过识别新类型的上皮细胞，我们将确定胸腺的哪些部分负责其功能。此外，通过发现胸腺在健康和骨髓移植后如何产生不同类型的T细胞，我们将能够操纵和监测胸腺功能。通过鉴定控制胸腺健康中胸腺的机制，我们将能够确定新的靶标，以增强疾病中的百里香功能。最终，我们的研究将意味着我们将对免疫系统中必不可少的器官起作用的方式有更深入的了解，然后我们可以用来设计纠正或改善多种免疫疾病的更好，更有效，更有效，更特定的疗法。

项目成果

A novel method to identify Post-Aire stages of medullary thymic epithelial cell differentiation.

• DOI: 10.1002/eji.202048764
• 发表时间: 2021-03
• 期刊: European journal of immunology
• 影响因子: 5.4
• 作者: Ferreirinha P;Ribeiro C;Morimoto J;Landry JJM;Matsumoto M;Meireles C;White AJ;Ohigashi I;Araújo L;Benes V;Takahama Y;Anderson G;Matsumoto M;Alves NL
• 通讯作者: Alves NL

Eosinophils are an essential element of a type 2 immune axis that controls thymus regeneration.

• DOI: 10.1126/sciimmunol.abn3286
• 发表时间: 2022-03-11
• 期刊: Science immunology
• 影响因子: 24.8
• 作者: Cosway EJ;White AJ;Parnell SM;Schweighoffer E;Jolin HE;Bacon A;Rodewald HR;Tybulewicz V;McKenzie ANJ;Jenkinson WE;Anderson G
• 通讯作者: Anderson G

The alarmin IL33 orchestrates type 2 immune-mediated control of thymus regeneration.

• DOI: 10.1038/s41467-023-43072-x
• 发表时间: 2023-11-08
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Cosway, Emilie J.;James, Kieran D.;White, Andrea J.;Parnell, Sonia M.;Bacon, Andrea;Mckenzie, Andrew N. J.;Jenkinson, W. E.;Anderson, Graham
• 通讯作者: Anderson, Graham

The medulla controls effector primed ?dT-cell development in the adult mouse thymus.

髓质控制成年小鼠胸腺中效应器引发的 dT 细胞的发育。

• DOI: 10.1002/eji.202350388
• 发表时间: 2023
• 期刊: European journal of immunology
• 影响因子: 5.4
• 作者: James KD

Assembling the thymus medulla: Development and function of epithelial cell heterogeneity

• DOI: 10.1002/bies.202300165
• 发表时间: 2023-12-31
• 期刊: BIOESSAYS
• 影响因子: 4
• 作者: James，Kieran D.;Cosway，Emilie J.;Anderson，Graham
• 通讯作者: Anderson，Graham