USE OF LOW-DOSE IL-2 TO EXPAND ENDOGENOUS REGULATORY T CELLS AND ACHIEVE TRANSPLANTATION TOLERANCE

使用低剂量 IL-2 扩增内源性调节 T 细胞并实现移植耐受

• 批准号: MR/P007694/1
• 负责人: Alberto Sanchez-Fueyo
• 金额: $ 104.72万
• 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: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FP007694%2F1
• 关键词: USE; LOW; DOSE; IL; EXPAND

A population of immune cells, called regulatory T cells or Tregs, have been shown in experimental animal models to regulate the immune system and to play a central role in preventing organ rejection and in controlling autoimmune and inflammatory diseases. In animal models of transplantation, Tregs are key to induce immunological tolerance, a situation in which the transplanted organ is indefinitely accepted in the absence of anti-rejection medication. The use of IL-2 at low doses has been shown to selectively and safely increase the number of Tregs in humans, but whether this can be used to induce tolerance in transplanted patients has never been investigated. Liver transplantation is an optimal clinical setting to do so, given that there are evidences indicating that transplantation tolerance can spontaneously occur in these patients (albeit only many years after transplantation), and that liver transplantation is the only solid organ transplantation setting in which it is safe to investigate the development of tolerance by intentionally discontinuing all anti-rejection medications. Our hypothesis is that administration of a short course of low-dose IL-2 will transiently expand the number of Tregs and allow for the permanent discontinuation of anti-rejection medication. In the current project we propose to conduct a clinical study in which liver transplant recipients who have a very low probability of achieving tolerance spontaneously will receive daily injections of IL-2 during the period of time when their anti-rejection medication is gradually withdrawn. Patients will be carefully studied to investigate the following:1) Whether IL-2 is efficacious in expanding the number of Tregs in liver transplant patients. 2) Whether the expansion of Tregs in the circulation and/or the liver facilitates the successful discontinuation of anti-rejection medication.3) What are the effects of an increased number of Tregs in the immune system of a transplanted patient. Ultimately, the project will serve to clarify whether donor-specific Tregs are essential to establish transplantation tolerance, and the extent to which low-dose IL-2 is an effective strategy to promote this phenomenon. This will have implications for a number of other inflammatory diseases, and will open the door to future clinical trials in which low-dose IL-2 could used in combination with other tolerance-promoting medications.

在实验动物模型中，一群称为调节性T细胞或T细胞的免疫细胞已被证明可以调节免疫系统，并在预防器官排斥反应和控制自身免疫性疾病和炎症性疾病方面发挥核心作用。在移植的动物模型中，胸腺素是诱导免疫耐受的关键，在这种情况下，移植的器官在没有抗排斥药物的情况下被无限期地接受。使用低剂量的IL-2已被证明可以选择性和安全地增加人体中的T细胞数量，但这是否可以用于诱导移植患者的耐受性从未被研究过。肝移植是最佳的临床环境，因为有证据表明这些患者可以自发发生移植耐受（尽管仅在移植后许多年），并且肝移植是唯一的实体器官移植环境，其中通过故意停用所有抗排斥药物来研究耐受性的发展是安全的。我们的假设是，短期给予低剂量IL-2将暂时增加TCLs的数量，并允许永久停用抗排斥药物。在当前的项目中，我们建议进行一项临床研究，其中肝移植受者自发获得耐受的可能性非常低，在他们的抗排斥药物逐渐停用期间，每天注射IL-2。将对患者进行仔细研究以调查以下内容：1）IL-2是否有效地增加肝移植患者中的T细胞数量。2)是否在循环和/或肝脏中的THBG的扩张有助于成功停止抗排斥药物。3）THBG数量增加对移植患者免疫系统的影响。最终，该项目将有助于澄清供体特异性THBG是否对建立移植耐受性至关重要，以及低剂量IL-2在多大程度上是促进这一现象的有效策略。这将对许多其他炎症性疾病产生影响，并将为未来的临床试验打开大门，其中低剂量IL-2可以与其他促进耐受性的药物联合使用。

项目成果

Textbook of Liver Transplantation - A Multidisciplinary Approach

肝移植教科书 - 多学科方法

• DOI: 10.1007/978-3-030-82930-8_45
• 发表时间: 2022
• 作者: Lim T

Pediatric Hepatology and Liver Transplantation

小儿肝病学和肝移植

• DOI: 10.1007/978-3-319-96400-3_36
• 发表时间: 2019
• 作者: Feng S

On minor histocompatibility antigens, mixed chimerism, and transplantation tolerance.

关于次要组织相容性抗原、混合嵌合和移植耐受。

• DOI: 10.1111/ajt.16276
• 发表时间: 2021
• 期刊: official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
• 作者: Sánchez-Fueyo A

Pediatric Liver Transplantation

小儿肝移植

• DOI: 10.1016/b978-0-323-63671-1.00045-8
• 发表时间: 2021
• 作者: Sanchez-Fueyo A

Liver transplantation immunology: Immunosuppression, rejection, and immunomodulation.

• DOI: 10.1016/j.jhep.2023.01.030
• 发表时间: 2023-06
• 期刊: Journal of hepatology
• 影响因子: 25.7
• 作者: A. Montaño-Loza;M. Rodríguez-Perálvarez;G. Pageaux;A. Sánchez‐Fueyo;S. Feng