德国柏林查理特大学Petra Reinke团队研究了调节性T细胞在肾移植中降低免疫抑制的效果。2020年10月21日，该研究发表在《英国医学杂志》上。

为了评估在肾移植后通过输注自体自然调节性T细胞（nTregs）来重塑免疫平衡是否安全可行，并减少终生高剂量的免疫抑制治疗（疗效有限、不良反应、费用高昂），以及解决nTreg治疗的几个关键挑战，例如简便有效的制备方法，过度免疫抑制的危险，与标准治疗药物的相互作用，以及在炎性环境中的功能稳定性，研究组进行了一项研究者发起、单中心、nTreg剂量递增、I / IIa期临床试验。

该研究在德国柏林的查理特大学医院进行，共招募了20例接受活体供肾移植的患者，其中11例接受nTregs治疗，在肾脏移植后7天以0.5、1.0或2.5-3.0×10⁶细胞/ kg体重的静脉注射剂量给予CD4 + CD25 + FoxP3 + nTreg干预药物，随后逐步将三重免疫抑制减少至低剂量他克莫司单药治疗，直至第48周。其余9例接受常规治疗，作为对照组。在第60周通过综合终点评估主要的临床和安全终点，并进一步随访三年。

对于所有患者，在肾脏移植前两周可从40-50 mL外周血中制备足够产量、纯度和功能的nTreg产品。三个nTreg剂量递增组中没有一例发生剂量限制性毒性。nTreg组和对照组的同种异体移植三年生存率均为100％，临床和安全性指标相差不大。

在接受nTreg治疗的11例患者中，有8例（73％）获得了稳定的单药免疫抑制，而对照组仍采用标准的双重或三重药物免疫抑制，差异显著。从机制上讲，常规T细胞激活减少，体内nTregs从多克隆转变为寡克隆T细胞受体。

研究结果表明，自体nTregs治疗肾脏移植患者安全可行，可显著降低移植后免疫抑制药物的剂量。

附：英文原文

Title: Regulatory T cells for minimising immune suppression in kidney transplantation: phase I/IIa clinical trial

Author: Andy Roemhild, Natalie Maureen Otto, Guido Moll, Mohamed Abou-El-Enein, Daniel Kaiser, Gantuja Bold, Thomas Schachtner, Mira Choi, Robert Oellinger, Sybille Landwehr-Kenzel, Karsten Juerchott, Birgit Sawitzki, Cordula Giesler, Anett Sefrin, Carola Beier, Dimitrios Laurin Wagner, Stephan Schlickeiser, Mathias Streitz, Michael Schmueck-Henneresse, Leila Amini, Ulrik Stervbo, Nina Babel, Hans-Dieter Volk, Petra Reinke

Issue&Volume: 2020/10/21

Abstract:

Objective To assess whether reshaping of the immune balance by infusion of autologous natural regulatory T cells (nTregs) in patients after kidney transplantation is safe, feasible, and enables the tapering of lifelong high dose immunosuppression, with its limited efficacy, adverse effects, and high direct and indirect costs, along with addressing several key challenges of nTreg treatment, such as easy and robust manufacturing, danger of over immunosuppression, interaction with standard care drugs, and functional stability in an inflammatory environment in a useful proof-of-concept disease model.

Design Investigator initiated, monocentre, nTreg dose escalation, phase I/IIa clinical trial (ONEnTreg13).

Setting Charité-University Hospital, Berlin, Germany, within the ONE study consortium (funded by the European Union).

Participants Recipients of living donor kidney transplant (ONEnTreg13, n=11) and corresponding reference group trial (ONErgt11-CHA, n=9).

Interventions CD4+ CD25+ FoxP3+ nTreg products were given seven days after kidney transplantation as one intravenous dose of 0.5, 1.0, or 2.5-3.0×106 cells/kg body weight, with subsequent stepwise tapering of triple immunosuppression to low dose tacrolimus monotherapy until week 48.

Main outcome measures The primary clinical and safety endpoints were assessed by a composite endpoint at week 60 with further three year follow-up. The assessment included incidence of biopsy confirmed acute rejection, assessment of nTreg infusion related adverse effects, and signs of over immunosuppression. Secondary endpoints addressed allograft functions. Accompanying research included a comprehensive exploratory biomarker portfolio.

Results For all patients, nTreg products with sufficient yield, purity, and functionality could be generated from 40-50 mL of peripheral blood taken two weeks before kidney transplantation. None of the three nTreg dose escalation groups had dose limiting toxicity. The nTreg and reference groups had 100% three year allograft survival and similar clinical and safety profiles. Stable monotherapy immunosuppression was achieved in eight of 11 (73%) patients receiving nTregs, while the reference group remained on standard dual or triple drug immunosuppression (P=0.002). Mechanistically, the activation of conventional T cells was reduced and nTregs shifted in vivo from a polyclonal to an oligoclonal T cell receptor repertoire.

Conclusions The application of autologous nTregs was safe and feasible even in patients who had a kidney transplant and were immunosuppressed. These results warrant further evaluation of Treg efficacy and serve as the basis for the development of next generation nTreg approaches in transplantation and any immunopathologies.

DOI: 10.1136/bmj.m3734

Source: https://www.bmj.com/content/371/bmj.m3734