Mesenchymal stem cells together with mycophenolate mofetil inhibit antigen presenting cell and T cell infiltration into allogeneic heart grafts.

Donor-derived mesenchymal stem cells (MSC) can induce long-term acceptance in a rat heart transplantation model when injected prior to transplantation in combination with mycophenolate mofetil (MMF). In contrast, MSC alone cause accelerated graft rejection. To better understand these conflicting data we studied the effects of MSC and MMF on lymphocyte populations in heart allografts and secondary lymphatic organs. Allogeneic MSC injected prior to transplantation are immunogenic in this model because activated CD4+ and CD8+ cells emerged earlier in secondary lymphatic organs of MSC- and MSC/MMF-treated animals, compared to animals not treated with MSC. Consequently T cells infiltrated the grafts of MSC-only treated animals promptly causing accelerated graft rejection. However, few T cells or antigen-presenting cells (APC) infiltrated the grafts of animals treated with MSC and MMF. Consistent with this finding, intercellular adhesion molecule 1 (ICAM-1) and E-selectin was down-regulated exclusively in MSC/MMF-treated grafts, indicating that MSC together with MMF interfere with endothelial activation. Additionally, the presence of interferon-gamma (IFN-γ) enhanced MSC capabilities to suppress T cell proliferation in vitro. Interestingly, MMF did not influence serum IFN-γ levels in vivo. Together, our data indicate that MSC pre-activate T cells, but co-treatment with MMF eliminates these T cells, decreases intragraft APC and T cell trafficking by inhibiting endothelial activation, and allows IFN-γ stimulation of suppressive MSC.

Mesenchymal stem cells require a sufficient, ongoing immune response to exert their immunosuppressive function.

Mesenchymal stem cells (MSC) have emerged to be one of the most promising candidates for cellular immunotherapy in solid organ transplantation because the reduction of conventional immunosuppression is highly desirable. However, little is known about the details of MSC-mediated immunomodulation and their clinical relevance. To address conflicting studies about the ability of MSC to suppress or augment T-cell proliferation, we introduce a transplantation-related rat model that allows studying the influence of MSC on alloproliferation. Hearts transplanted in a fully allogeneic transplantation model (LEW to ACI) were rejected earlier when recipients were pretreated with donor MSC, indicating activation of T cells in vivo. In additional co-culture experiments, T cells were differently affected by allogeneic MSC depending on the extent of previous activation: When conditions were rendered proinflammatory by adding high concanavalin A (ConA) concentrations or proinflammatory cytokines (interferon-gamma, interleukin-2, or tumor necrosis factor-alpha), MSC inhibited proliferation. Application of low doses of ConA or anti-inflammatory cytokines like IL-10 abrogated the suppressive effect of MSC. For application of MSC in solid organ transplantation, it will be important to further describe this switch effect of MSC function.