Berlin-Brandenburg Center for Regenerative Therapies, Charité University Medicine Berlin, Berlin, Germany; Berlin-Brandenburg School for Regenerative Therapies, Charité University Medicine Berlin, Berlin, Germany; Department of Pediatrics, Division of Pneumonology and Immunology, Charité University Medicine Berlin, Berlin, Germany.
Berlin-Brandenburg Center for Regenerative Therapies, Charité University Medicine Berlin, Berlin, Germany; Renal and Transplant Research Unit, Department of Nephrology and Internal Intensive Care, Charité University Medicine Berlin, Berlin, Germany.
Kidney Int. 2018 Jun;93(6):1452-1464. doi: 10.1016/j.kint.2018.01.021.
Novel concepts employing autologous, ex vivo expanded natural regulatory T cells (nTreg) for adoptive transfer has potential to prevent organ rejection after kidney transplantation. However, the impact of dialysis and maintenance immunosuppression on the nTreg phenotype and peripheral survival is not well understood, but essential when assessing patient eligibility. The current study investigates regulatory T-cells in dialysis and kidney transplanted patients and the feasibility of generating a clinically useful nTreg product from these patients. Heparinized blood from 200 individuals including healthy controls, dialysis patients with end stage renal disease and patients 1, 5, 10, 15, 20 years after kidney transplantation were analyzed. Differentiation and maturation of nTregs were studied by flow cytometry in order to compare dialysis patients and kidney transplanted patients under maintenance immunosuppression to healthy controls. CD127 expressing CD4CD25FoxP3 nTregs were detectable at increased frequencies in dialysis patients with no negative impact on the nTreg end product quality and therapeutic usefulness of the ex vivo expanded nTregs. Further, despite that immunosuppression mildly altered nTreg maturation, neither dialysis nor pharmacological immunosuppression or previous acute rejection episodes impeded nTreg survival in vivo. Accordingly, the generation of autologous, highly pure nTreg products is feasible and qualifies patients awaiting or having received allogenic kidney transplantation for adoptive nTreg therapy. Thus, our novel treatment approach may enable us to reduce the incidence of organ rejection and reduce the need of long-term immunosuppression.
采用自体、体外扩增的天然调节性 T 细胞（nTreg）进行过继转移的新概念有可能预防肾移植后的器官排斥。然而，透析和维持性免疫抑制对 nTreg 表型和外周存活的影响尚不清楚，但在评估患者资格时至关重要。本研究调查了透析和肾移植患者中的调节性 T 细胞，以及从这些患者中产生临床有用的 nTreg 产品的可行性。分析了包括健康对照者、终末期肾病透析患者和肾移植后 1、5、10、15、20 年的患者在内的 200 个人的肝素化血液。通过流式细胞术研究 nTreg 的分化和成熟，以比较维持性免疫抑制下的透析患者和肾移植患者与健康对照者。在透析患者中可检测到表达 CD127 的 CD4CD25FoxP3 nTreg 的频率增加，对 nTreg 终产物质量和体外扩增的 nTreg 的治疗用途没有负面影响。此外，尽管免疫抑制轻度改变了 nTreg 的成熟，但透析、药物免疫抑制或先前的急性排斥反应事件均未阻碍 nTreg 在体内的存活。因此，自体、高纯度 nTreg 产品的产生是可行的，并使等待或已接受同种异体肾移植的患者有资格接受过继性 nTreg 治疗。因此，我们的新治疗方法可能使我们能够降低器官排斥的发生率，并减少长期免疫抑制的需求。
