Mesenchymal stromal cells derived microvesicles as inductors of immune tolerance

Abstract

The solid organ transplantation is the best therapeutic option for patients with end-organ failures. However, this treatment risks infections and a range of side-effects, which, together with the inexorable chronic allograft injury, limit the graft and patient survival. These findings highlight the urgent need for more effective and less toxic treatments to improve the outcome of solid organ transplantation. Mesenchymal Stromal Cells (MSC) have recently emerged as one of the most promising candidates for cell-based immunotherapy because they modulate the immune response in several ways. Microvesicles (MVs) released by MSCs are one of the main responsible for the therapeutic effects of these cells and replacing MVs by MSCs in treatments can be viable and offers greater security. Recently, it has been demonstrated that, in the presence of pro-inflammatory cytokines, the inhibitory effect of MSC increases, leading to the idea that an appropriate inflammatory environment license MSC to exert their inhibitory actions. Just as MSCs are influenced by the inflammatory microenvironment, the same can happen with MVs, changing its content and its action. The present study will test the hypothesis that pre-activation of MSC in-vitro could be a strategy to alter the profile of MVs and hence their immunosuppressive capacity in vitro and in vivo in allogeneic immune responses. To pursue this goal, MVs will be obtained from IFNg-treated-MSC and following their role in T cell suppression, Treg and regulatory DCs generation will be studied in vitro and in vivo skin transplantation model. We expect that MVs from activated MSC will be the crucial mechanism of action in MSC-induced immunomodulation, on purpose to induce immune tolerance in a skin transplant model. Thus, this represents a step forward to with live cells therapy enhancing survival of transplanted organs and patients. (AU)