Abstract
BackgroundMesenchymal stromal cells (MSC) may serve as an attractive therapy in renal transplantation due to their immunosuppressive and reparative properties. While most studies have used autologous MSCs, allogeneic MSCs offer the advantage of immediate availability for clinical use. This is of major importance for indications where instant treatment is needed, for example allograft rejection or calcineurin inhibitor toxicity. Clinical studies using allogeneic MSCs are limited in number. Although these studies showed no adverse reactions, allogeneic MSCs could possibly elicit an anti-donor immune response, which may increase the incidence of rejection and impact the allograft survival in the long term. These safety issues should be addressed before further studies are planned with allogeneic MSCs in the solid organ transplant setting.Methods/design10 renal allograft recipients, 18–75 years old, will be included in this clinical phase Ib, open label, single center study. Patients will receive two doses of 1.5 × 106 per/kg body weight allogeneic bone marrow derived MSCs intravenously, at 25 and 26 weeks after transplantation, when immune suppression levels are reduced. The primary end point of this study is safety by assessing biopsy proven acute rejection (BPAR)/graft loss after MSC treatment. Secondary end points, all measured before and after MSC infusions, include: comparison of fibrosis in renal biopsy by quantitative Sirius Red scoring; de novo HLA antibody development and extensive immune monitoring; renal function measured by cGFR and iohexol clearance; CMV and BK infection and other opportunistic infections.DiscussionThis study will provide information on the safety of allogeneic MSC infusion and its effect on the incidence of BPAR/graft loss.Trial registration: NCT02387151
Highlights
Mesenchymal stromal cells (MSC) may serve as an attractive therapy in renal transplantation due to their immunosuppressive and reparative properties
In renal transplantation MSC therapy could be attractive in view of its potent effects on immune cells and its reparative properties
We envisage that this could be a step forward to prolong allograft survival. In this phase I study we will test whether the administration of selected allogeneic MSCs is safe and does not increase the incidence of biopsy proven acute rejection (BPAR) and/or graft loss
Summary
Overall kidney graft survival has improved over the past decades, mainly as a result of improvement of first-year graft survival due to better immunosuppressive regimens and overall medical care. In vitro studies imply that MSCs may play a role in modulation of immune responses These beneficial immune modulatory effects have been confirmed in experimental models of allo- and autoimmune disorders, including allograft rejection [10,11,12,13,14]. It is necessary that we establish whether allogeneic MSC therapy in renal recipients is safe and does not evoke an anti-donor response, which might negatively impact graft function and survival. To minimize the chance of development of anti-donor immune responses and allograft rejection our strategy is to select allogeneic MSCs, which have no similarity with the HLA mismatches between the kidney graft and the recipient. A second criteria is that the recipient should have no preformed HLA antibodies directed to the MSCs in order to prevent immune destruction of the MSCs
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