Interaction between adipose tissue-derived mesenchymal stem cells and regulatory T-cells

Mesenchymal stem cells (MSCs) exhibit immunosuppressive capabilities, which have evoked interest in their application as cell therapy in transplant patients. So far it has been unclear whether allogeneic MSCs and host regulatory T-cells (Tregs) functionally influence each other. We investigated the interaction between both cell types using perirenal adipose tissue-derived MSCs (ASCs) from kidney donors and Tregs from blood bank donors or kidney recipients 6 months after transplantation. The immunomodulatory capacity of ASCs was not prejudiced by both Tregs from healthy donors and Tregs from graft recipients, indicating that ASCs were not targeted by the inhibitory effects of Tregs and vice versa. In addition, Tregs supported ASC function, as they did not alter the secretion of IFN-γ by immune cells and hence contributed to ASC activation and efficiency. ASCs exerted their suppressive role by expressing IDO, reducing levels of TNF-α, and by inducing the production of IL-10 in effector cells and Tregs. In conclusion, this study presents evidence that donor ASCs and acceptor Tregs do not impair each other's function and therefore encourages the use of MSC therapy for the prevention of graft rejection in solid organ transplantation

Mesenchymal stem cells control alloreactive CD8+CD28- T cells

CD28/B7 co-stimulation blockade with belatacept prevents alloreactivity in kidney transplant patients. However, cells lacking CD28 are not susceptible to belatacept treatment. As CD8+CD28- T-cells have cytotoxic and pathogenic properties, we investigated whether mesenchymal stem cells (MSC) are effective in controlling these cells. In mixed lymphocyte reactions (MLR), MSC and belatacept inhibited peripheral blood mononuclear cell (PBMC) proliferation in a dose-dependent manner. MSC at MSC/effector cell ratios of 1:160 and 1:2·5 reduced proliferation by 38·8 and 92·2%, respectively. Belatacept concentrations of 0·1μg/ml and 10μg/ml suppressed proliferation by 20·7 and 80·6%, respectively. Both treatments in combination did not inhibit each other's function. Allostimulated CD8+CD28- T cells were able to proliferate and expressed the cytolytic and cytotoxic effector molecules granzyme B, interferon (IFN)-γ and tumour necrosis factor (TNF)-α. While belatacept did not affect the proliferation of CD8+CD28- T cells, MSC reduced the percentage of CD28- T cells in the proliferating CD8+ T cell fraction by 45·9% (P=0·009). CD8+CD28- T cells as effector cells in MLR in the presence of CD4+ T cell help gained CD28 expression, an effect independent of MSC. In contrast, allostimulated CD28+ T cells did not lose CD28 expression in MLR-MSC co-culture, suggesting that MSC control pre-existing CD28- T cells and not newly induced CD28- T cells. In conclusion, alloreactive CD8+CD28- T cells that remain unaffected by belatacept treatment are inhibited by MSC. This study indicates the potential of an MSC-belatacept combination therapy to control alloreactivity

Mesenchymal stem cells in solid organ transplantation (MiSOT) fourth meeting: Lessons learned from first clinical trials

The Fourth Expert Meeting of the Mesenchymal Stem Cells in Solid Organ Transplantation (MiSOT) Consortium took place in Barcelona on October 19 and 20, 2012. This meeting focused on the translation of preclinical data into early clinical settings. This position paper highlights the main topics explored on the safety and efficacy of mesenchymal stem cells as a therapeutic agent in solid organ transplantation and emphasizes the issues (proper timing, concomitant immunossupression, source and immunogenicity of mesenchymal stem cells, and oncogenicity) that have been addressed and will be followed up by the MiSOT Consortium in future studies