Mesenchymal stem cells exert immunosuppressive function depending on previous activation

Background: Mesenchymal stem cells (MSC) have emerged to be one of the most promising candidates for cellular immunotherapy in solid organ transplantation since the reduction of conventional immunosuppression is highly desirable. However, little is known about the details of MSC-mediated immunomodulation and their clinical relevance. Methods: To address conflicting studies about the ability of MSC to suppress or augment T-cell proliferation, we introduce transplantationrelated rat and mouse models that allow to study the influence of MSC on alloproliferation. Results: Hearts transplanted in fully allogeneic transplantation models (in rats and mice) were rejected earlier when recipients were treated with donor MSC, indicating activation of T cells in vivo. In additional coculture experiments, T cells were differently affected by allogeneic MSC depending on the extent of previous activation: when conditions were rendered proinflammatory by adding high ConA concentrations or proinflammatory cytokines (IFNγ, IL-2 or TNFα), MSC inhibited proliferation. Application of low doses of ConA or antiinflammatory cytokines like IL-10 abrogated the suppressive effect of MSC. Conclusion: For application of MSC in solid organ transplantation, it will be important to further describe the bimodal MSC function and define the micromilieu that drives MSC towards immune suppressive action.