Long-Term Clinical and Immunological Profile of Kidney Transplant Patients Given Mesenchymal Stromal Cell Immunotherapy.

Norberto Perico,Federica Casiraghi,Eliana Gotti,Alessandro Villa,Martino Introna,Marilena Mister,Sonia Fiori,Elena Longhi,Marta Todeschini,Valentina Portalupi,Giuseppe Remuzzi,Monica Cortinovis,Flavio Gaspari

doi:10.3389/fimmu.2018.01359

Abstract

We report here the long-term clinical and immunological results of four living-donor kidney transplant patients given autologous bone marrow-derived mesenchymal stromal cells (MSCs) as part of a phase 1 study focused on the safety and feasibility of this cell therapy. According to study protocols implemented over time, based on initial early safety findings, the patients were given MSC at day 7 posttransplant (n = 2) or at day −1 pretransplant (n = 2) and received induction therapy with basiliximab and low-dose rabbit anti-thymocyte globulin (RATG) or RATG alone, and were maintained on low-dose ciclosporin (CsA)/mycophenolate mofetil (MMF). All MSC-treated patients had stable graft function during the 5- to 7-year follow-up, without increased susceptibility to infections or neoplasm. In three MSC recipients, but not historical control patients, circulating memory CD8+ T cell percentages remained lower than basal, coupled with persistent reduction of ex vivo donor-specific cytotoxicity. Two patients showed a long-lasting increase in the regulatory T cell/memory CD8+ T cell ratio, paralleled by high circulating levels of naïve and transitional B cells. In one of these two patients, CsA was successfully discontinued, and currently the low-dose MMF monotherapy is on the tapering phase. The study shows that MSC therapy is safe in the long term and could promote a pro-tolerogenic environment in selected patients. Extensive immunomonitoring of MSC-treated kidney transplant recipients could help selection of patients for safe withdrawal of maintenance immunosuppressive drugs (NCT00752479 and NCT02012153).

Highlights

Kidney transplantation has become the treatment of choice for patients with end-stage renal disease (ESRD)
We report here that inducing long-term stable renal graft function under minimization of maintenance immunosuppressive therapy can be achieved after peri-transplant single infusion of autologous bone marrow-derived mesenchymal stromal cells (MSC)
The results of this study provided the first insights into the long-term in vivo effects of MSC infusion on peripheral lymphocyte subsets with effector and regulatory properties, as well as on host T cell allo-reactivity

Summary

Introduction

Kidney transplantation has become the treatment of choice for patients with end-stage renal disease (ESRD). The transplant community’s attention has shifted away from harmful immunosuppressive regimens toward identifying strategies to induce specific allograft tolerance, avoiding or limiting the need for conventional anti-rejection medications [4]. In this perspective, three medical centers are actively pursuing tolerance induction in recipients of living-donor kidney transplants by infusing donor hematopoietic stem cells to establish various levels of chimerism [5,6,7,8]. The risks of serious infections, graft-vs-host disease, and death, inherently associated with the procedures, clearly outweigh any potential benefits of tolerance, making these protocols too risky to justify routine use in patients without malignancies. Alternative immunomodulatory cell populations not requiring peri-transplant conditioning regimens are currently being investigated for use as immunotherapy in solid organ transplantation, including tolerogenic dendritic cells, regulatory macrophages, regulatory T cells (Tregs), and mesenchymal stromal cells (MSCs) [9, 10]

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Results

Conclusion