Efficacy and Safety of Bone Marrow-Derived Mesenchymal Stem Cells for Chronic Antibody-Mediated Rejection After Kidney Transplantation- A Single-Arm, Two-Dosing-Regimen, Phase I/II Study.

Jiali Wang ,Andy Peng Xiang,Ronghai Deng,Qian Fu,Yanwen Peng,Xiaoran Zhang,Huiting Huang,Yingnan Wei ,Qianyu Ye,Jun Li,Gang Li ,Xiaoyong Chen ,Shicong Yang,Yifang Gao,Qun Su,Chunrui Wu ,Changxi Wang,Huanxi Zhang,Longshan Liu,Bowen Xu,Xirui Li,Xiaojun Su

doi:10.3389/fimmu.2021.662441

Abstract

ObjectiveTo investigate the efficacy and safety of bone marrow-derived mesenchymal stem cells (BM-MSCs) on chronic active antibody-mediated rejection (cABMR) in the kidney allograft.MethodsKidney recipients with biopsy-proven cABMR were treated with allogeneic third-party BM-MSCs in this open-label, single-arm, single-center, two-dosing-regimen phase I/II clinical trial. In Regimen 1 (n=8), BM-MSCs were administered intravenously at a dose of 1.0×106 cells/kg monthly for four consecutive months, while in Regimen 2 (n=15), the BM-MSCs dose was 1.0×106 cells/kg weekly during four consecutive weeks. The primary endpoints were the absolute change of estimated glomerular filtration rate (eGFR) from baseline (delta eGFR) and the incidence of adverse events associated with BM-MSCs administration 24 months after the treatment. Contemporaneous cABMR patients who did not receive BM-MSCs were retrospectively analyzed as the control group (n =30).ResultsTwenty-three recipients with cABMR received BM-MSCs. The median delta eGFR of the total BM-MSCs treated patients was -4.3 ml/min per 1.73m2 (interquartile range, IQR -11.2 to 1.2) 2 years after BM-MSCs treatment (P=0.0233). The median delta maximum donor-specific antibody (maxDSA) was -4310 (IQR -9187 to 1129) at 2 years (P=0.0040). The median delta eGFR of the control group was -12.7 ml/min per 1.73 m2 (IQR -22.2 to -3.5) 2 years after the diagnosis, which was greater than that of the BM-MSCs treated group (P=0.0342). The incidence of hepatic enzyme elevation, BK polyomaviruses (BKV) infection, cytomegalovirus (CMV) infection was 17.4%, 17.4%, 8.7%, respectively. There was no fever, anaphylaxis, phlebitis or venous thrombosis, cardiovascular complications, or malignancy after BM-MSCs administration. Flow cytometry analysis showed a significant decreasing trend of CD27-IgD- double negative B cells subsets and trend towards the increase of CD3+CD4+PD-1+/lymphocyte population after MSCs therapy. Multiplex analysis found TNF-α, CXCL10, CCL4, CCL11 and RANTES decreased after MSCs treatment.ConclusionKidney allograft recipients with cABMR are tolerable to BM-MSCs. Immunosuppressive drugs combined with intravenous BM-MSCs can delay the deterioration of allograft function, probably by decreasing DSA level and reducing DSA-induced injury. The underlying mechanism may involve immunomodulatory effect of MSCs on peripheral B and T cells subsets.

Highlights

Kidney transplantation is the most effective treatment for endstage renal disease (ESRD) as it can significantly prolong life expectancy and improve life quality of patients with ESRD
Other medications used for cABMR before or after MSCs treatment are listed in Supplemental Table 1
A previous multi-centered study has demonstrated that the estimated glomerular filtration rate (eGFR) of patients with biopsy-proven late active Antibodymediated rejection (ABMR) significantly declines by a delta value of -9.084 ml/min per 1.73m2 one year after cABMR diagnosis [21]

Summary

Introduction

Kidney transplantation is the most effective treatment for endstage renal disease (ESRD) as it can significantly prolong life expectancy and improve life quality of patients with ESRD. The 1-year graft survival rate has increased to nearly 95%. Long-term survival is still unsatisfactory, and the 10-year graft survival rate is nearly 60% [1]. Antibodymediated rejection (ABMR) is the main cause of long-term graft loss after kidney transplantation [2]. B cells can be activated under many circumstances prior to or after transplantation to produce donor-specific antibodies (DSA) which are mainly antiHLA (human leukocyte antigen) antibodies. The DSA attack vascular endothelium of renal allografts through complementdependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) pathways, causing microvascular inflammation and leading, to chronic damage, in the long-term including transplant glomerulopathy, arterial intimal thickening, renal tubular atrophy and interstitial fibrosis, etc [3]

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Conclusion