MSCs in renal transplantation

Kidney transplantation has improved survival and quality of life for patients with end-stage renal disease. However, despite advances in immunosuppressive therapy, long-term allograft survival outcomes have not improved over the last decade. Thus there remains a need for therapeutic alternatives because patients may not respond to existing therapeutic choices, they do not show an improvement of the fibrosis reaction or an effect on long term survival, or they may develop immunosuppression induced serious (sometimes fatal) side effects and toxicities. A promising novel therapeutic immunosuppressive option in the treatment of renal recipients with a profound effect on the fibrosis reaction and fewer side effects than existing immunosuppressive therapies is the clinical application of mesenchymal stromal cells (MSCs). In contrast to most current pharmacological agents that target only a single pathophysiological pathway, MSCs potentially affect immunologic, inflammatory, vascular and regenerative pathways, which provide an exciting opportunity for further research. In vitro studies imply that MSCs may play a role in modulation of immune responses and beneficial immunomodulatory effects of MSCs have been shown in models of experimental allo- and autoimmune disorders, including allograft rejection. After human renal transplantation, first results demonstrate safety, feasibility and an indication for immunosuppressive capacities of autologous bone marrow derived MSCs. In renal recipients, MSCs might play roles in the treatment of allograft rejection and fibrosis, and in calcineurin minimization and induction protocols. At the LUMC a new study has been started which will will test the hypothesis that MSCs in combination with Everolimus facilitate tacrolimus withdrawal, reduce fibrosis and decrease the incidence of opportunistic infections compared to standard tacrolimus dose. As MSCs are immunoprivileged, both autologous and allogeneic therapies are possible, but most studies have used autologous cells. Allogeneic MSCs offer the advantage of availability for clinical use without the delay required for expansion. This is of major importance in the case of indications where treatment is needed without delay, for example in allograft rejection of the transplanted organ. Although it is believed that allo MSCs are immune privileged, they could possibly elicit an anti-donor immune response, which may increase the incidence of rejection/ graft loss and impact the allograft survival on the long term. These safety issues should be studied before further studies are planned with allogeneic MSCs in the transplant setting.