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
Open Access
- 25 June 2021
- journal article
- research article
- Published by Frontiers Media SA in Frontiers in Immunology
Abstract
Objective To 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. Methods Kidney 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). Results Twenty-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. Conclusion Kidney 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.This publication has 52 references indexed in Scilit:
- The Banff 2019 Kidney Meeting Report (I): Updates on and clarification of criteria for T cell– and antibody-mediated rejectionAmerican Journal of Transplantation, 2020
- Recommended Treatment for Antibody-mediated Rejection After Kidney Transplantation: The 2019 Expert Consensus From the Transplantion Society Working GroupTransplantation, 2020
- Antibody-Mediated Rejection of Solid-Organ AllograftsThe New England Journal of Medicine, 2018
- Mesenchymal Stromal Cells: Clinical Challenges and Therapeutic OpportunitiesCell Stem Cell, 2018
- Allogeneic mesenchymal stem cells as induction therapy are safe and feasible in renal allografts: pilot results of a multicenter randomized controlled trialJournal of Translational Medicine, 2018
- Mesenchymal stromal cells in renal transplantation: opportunities and challengesNature Reviews Nephrology, 2016
- OPTN/SRTR 2013 Annual Data Report: KidneyAmerican Journal of Transplantation, 2015
- Complement-Binding Anti-HLA Antibodies and Kidney-Allograft SurvivalThe New England Journal of Medicine, 2013
- Induction Therapy With Autologous Mesenchymal Stem Cells in Living-Related Kidney TransplantsJAMA, 2012
- Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cellsThe Lancet, 2004