調節性T細胞治療腎移植患者可顯著降低免疫抑制劑的使用
作者：
小柯機器人發布時間：2020/10/25 22:07:58
德國柏林查理特大學Petra Reinke團隊研究了調節性T細胞在腎移植中降低免疫抑制的效果。2020年10月21日，該研究發表在《英國醫學雜誌》上。
為了評估在腎移植後通過輸注自體自然調節性T細胞（nTregs）來重塑免疫平衡是否安全可行，並減少終生高劑量的免疫抑制治療（療效有限、不良反應、費用高昂），以及解決nTreg治療的幾個關鍵挑戰，例如簡便有效的製備方法，過度免疫抑制的危險，與標準治療藥物的相互作用，以及在炎性環境中的功能穩定性，研究組進行了一項研究者發起、單中心、nTreg劑量遞增、I / IIa期臨床試驗。
該研究在德國柏林的查理特大學醫院進行，共招募了20例接受活體供腎移植的患者，其中11例接受nTregs治療，在腎臟移植後7天以0.5、1.0或2.5-3.0×106細胞/ kg體重的靜脈注射劑量給予CD4 + CD25 + FoxP3 + nTreg幹預藥物，隨後逐步將三重免疫抑制減少至低劑量他克莫司單藥治療，直至第48周。其餘9例接受常規治療，作為對照組。在第60周通過綜合終點評估主要的臨床和安全終點，並進一步隨訪三年。
對於所有患者，在腎臟移植前兩周可從40-50 mL外周血中製備足夠產量、純度和功能的nTreg產品。三個nTreg劑量遞增組中沒有一例發生劑量限制性毒性。nTreg組和對照組的同種異體移植三年生存率均為100％，臨床和安全性指標相差不大。
在接受nTreg治療的11例患者中，有8例（73％）獲得了穩定的單藥免疫抑制，而對照組仍採用標準的雙重或三重藥物免疫抑制，差異顯著。從機制上講，常規T細胞激活減少，體內nTregs從多克隆轉變為寡克隆T細胞受體。
研究結果表明，自體nTregs治療腎臟移植患者安全可行，可顯著降低移植後免疫抑制藥物的劑量。
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