Safinia Niloufar, Vaikunthanathan Trishan, Fraser Henrieta, Thirkell Sarah, Lowe Katie, Blackmore Laura, Whitehouse Gavin, Martinez-Llordella Marc, Jassem Wayel, Sanchez-Fueyo Alberto, Lechler Robert I, Lombardi Giovanna
MRC Centre for Transplantation, Division of Transplantation Immunology and Mucosal Biology, King's College London, Guy's Hospital, London, UK.
Institute of Liver Studies, King's College Hospital, London, UK.
Oncotarget. 2016 Feb 16;7(7):7563-77. doi: 10.18632/oncotarget.6927.
Strategies to prevent organ transplant rejection whilst minimizing long-term immunosuppression are currently under intense investigation with regulatory T cells (Tregs) nearing clinical application. The clinical trial, ThRIL, recently commenced at King's College London, proposes to use Treg cell therapy to induce tolerance in liver transplant recipients, the success of which has the potential to revolutionize the management of these patients and enable a future of drug-free transplants. This is the first report of the manufacture of clinical grade Tregs from prospective liver transplant recipients via a CliniMACS-based GMP isolation technique and expanded using anti-CD3/CD28 beads, IL-2 and rapamycin. We report the enrichment of a pure, stable population of Tregs (>95% CD4(+)CD25(+)FOXP3(+)), reaching adequate numbers for their clinical application. Our protocol proved successful in, influencing the expansion of superior functional Tregs, as compared to freshly isolated cells, whilst also preventing their conversion to Th17 cells under pro-inflammatory conditions. We conclude with the manufacture of the final Treg product in the clinical research facility (CRF), a prerequisite for the clinical application of these cells. The data presented in this manuscript together with the much-anticipated clinical results from ThRIL, will undoubtedly inform the improved management of the liver transplant recipient.
目前正在深入研究在尽量减少长期免疫抑制的同时预防器官移植排斥的策略，调节性T细胞（Tregs）已接近临床应用阶段。伦敦国王学院最近启动了一项名为ThRIL的临床试验，该试验计划使用Treg细胞疗法诱导肝移植受者产生免疫耐受，其成功可能会彻底改变这些患者的治疗方式，并实现无药物移植的未来。这是首篇关于通过基于CliniMACS的GMP分离技术，从预期的肝移植受者中制备临床级Tregs，并使用抗CD3/CD28磁珠、白细胞介素-2和雷帕霉素进行扩增的报告。我们报告了富集出了纯度高、稳定性好的Tregs群体（>95% CD4(+)CD25(+)FOXP3(+)），数量足以用于临床应用。与新鲜分离的细胞相比，我们的方案成功地影响了功能优越的Tregs的扩增，同时还防止了它们在促炎条件下转化为Th17细胞。我们在临床研究设施（CRF）中完成了最终Treg产品的制备，这是这些细胞临床应用的先决条件。本手稿中呈现的数据以及ThRIL备受期待的临床结果，无疑将为改善肝移植受者的管理提供参考。
