A high-throughput-compatible animal-cell-free miniaturised thymic organoid model for thymus biology studies and in vitro T cell production.

一种高通量兼容的无动物细胞小型胸腺类器官模型，用于胸腺生物学研究和体外 T 细胞生产。

• 批准号: NC/X002470/1
• 负责人: Clare Blackburn
• 金额: $ 25.52万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=NC%2FX002470%2F1
• 关键词: throughput; compatible; animal; cell; free

T cells, a type of white blood cell, are an essential component of our immune system. They coordinate and effect our immune responses so we can control infections. Controlling different infections requires different types of immune response and our T cells allow us to make specific immune responses to specific infections. Recently, the power of T cells has been harnessed in medicine to make a new type of therapy called immunotherapy. Immunotherapies are still in their infancy, but have already been used successfully to treat some blood cancers.Within the body, T cells can only be made in a highly specialised organ, the thymus. The thymus instructs precursor cells in the blood to become T cells, then guides the developing T cells through a series of screening processes that ensure that only safe, functional T cells leave the thymus to become part of the immune system. These processes are needed because each T cell has on its surface a protein called T cell receptor (TCR). The TCR recognises and binds a small part of a specific protein (called a peptide) on the surface of other, non-T, cells. When T cells are developing, a very large number of different TCRs are made, that each recognise a peptide from a different protein. Each T cell has a different TCR. Some of the TCRs that are made can bind peptides from proteins from infectious agents such as viruses. Other TCRs can bind peptides from proteins in our own bodies. If these 'self-reactive' TCRs became part of our immune systems they would cause autoimmunity and to avoid this, they are screened out in the thymus. This screening is performed by special cells in the thymus called thymic epithelial cells, which can selectively remove or disarm 'self-reactive' T cells. The thymus is one of the first organs to degenerate in healthy individuals, and this contributes to a general decline in immune system function with age. This is one of the major reasons that as we get older we become more susceptible to new infections, such as flu and covid19. Thymus degeneration also causes problems for adult patients requiring a bone marrow transplant (BMT). This is because, after transplant, some patients take several years to make enough T cells again and these individuals remain vulnerable to infections until their immune system has been properly rebuilt. If their thymus function could be boosted, this time would be shortened.All of this together means there is a lot of interest in making T cells in the lab (eg. for immunotherapy) and in developing methods for boosting thymus function in patients (including BMT patients and the elderly), to increase their ability to fight new infections. However, at present, the only experimental models that mimic thymus function sufficiently well for these purposes rely on the use of cells obtained from the native thymus. Thymus tissue is scarce and hard to work with, which severely limits the numbers and size of studies that can currently be performed - for instance high throughput screening for new drugs relevant to thymus regeneration is not currently possible. We have recently shown that thymic epithelial cells can be made in the lab, starting from stem cells. We have also shown that we can grow miniaturized thymus organs (MTOs), in the lab, starting from native thymus tissue. We make these MTOs in a format that is suitable for low, medium and high throughput studies including drug screening and lab based T cell production. However, their use is still limited by tissue supply. This project will test whether we can combine these two approaches to make fully animal-cell-free MTOs from stem cells. If successful, this new animal-cell-free model system will significantly reduce the number of animals used in research. It will also enable a new era of thymus research in which much larger scale experiments can easily be performed, opening up this area to a wide range of laboratories including the pharmaceutical industry.

T细胞是一种白细胞，是我们免疫系统的重要组成部分。它们协调和影响我们的免疫反应，使我们能够控制感染。控制不同的感染需要不同类型的免疫反应，我们的T细胞允许我们对特定的感染做出特定的免疫反应。最近，T细胞的力量在医学上被用来制造一种叫做免疫疗法的新型疗法。免疫疗法仍处于起步阶段，但已经成功地用于治疗一些血癌。在人体内，T细胞只能在一个高度特化的器官胸腺中产生。胸腺引导血液中的前体细胞变成T细胞，然后引导正在发育的T细胞通过一系列筛选过程，以确保只有安全、有功能的T细胞离开胸腺，成为免疫系统的一部分。这些过程是必需的，因为每个T细胞表面都有一种叫做T细胞受体（TCR）的蛋白质。TCR识别并结合其他非t细胞表面的一小部分特定蛋白质（称为肽）。当T细胞发育时，会产生大量不同的tcr，每个tcr都能识别来自不同蛋白质的肽。每个T细胞都有不同的TCR。一些合成的tcr可以结合来自传染源（如病毒）的蛋白质的肽。其他tcr可以结合我们体内蛋白质的肽。如果这些“自我反应”的tcr成为我们免疫系统的一部分，它们会引起自身免疫，为了避免这种情况，它们会在胸腺中被筛选出来。这种筛选是由胸腺中一种叫做胸腺上皮细胞的特殊细胞进行的，这种细胞可以选择性地去除或解除“自我反应”T细胞的武装。在健康个体中，胸腺是最先退化的器官之一，这导致免疫系统功能随着年龄的增长而普遍下降。这是随着年龄的增长，我们更容易受到流感和covid - 19等新感染的主要原因之一。胸腺退化也会给需要骨髓移植（BMT）的成年患者带来问题。这是因为，在移植后，一些患者需要几年的时间才能再次产生足够的T细胞，这些人在免疫系统得到适当重建之前仍然容易受到感染。如果能增强胸腺功能，这个时间就会缩短。所有这些结合在一起意味着在实验室中制造T细胞有很多兴趣。在免疫治疗方面)，以及开发增强患者（包括BMT患者和老年人）胸腺功能的方法，以提高他们抵抗新感染的能力。然而，目前，唯一能够充分模拟胸腺功能的实验模型依赖于使用从天然胸腺中获得的细胞。胸腺组织是稀缺的，很难处理，这严重限制了目前可以进行的研究的数量和规模——例如，目前不可能对胸腺再生相关的新药进行高通量筛选。我们最近已经证明，胸腺上皮细胞可以在实验室中从干细胞开始制造。我们也已经证明，我们可以在实验室中，从原生胸腺组织开始，培养微型胸腺器官（MTOs）。我们以适合低、中、高通量研究的格式制作这些mto，包括药物筛选和基于实验室的T细胞生产。然而，它们的使用仍然受到组织供应的限制。这个项目将测试我们是否可以将这两种方法结合起来，从干细胞中制造完全不含动物细胞的mto。如果成功，这种新的动物无细胞模型系统将大大减少用于研究的动物数量。这也将开启一个胸腺研究的新时代，更大规模的实验可以很容易地进行，向包括制药工业在内的广泛实验室开放这一领域。