The Synergistic Immunoregulatory Effects of Culture-Expanded Mesenchymal Stromal Cells and CD4+25+Foxp3+ Regulatory T Cells on Skin Allograft Rejection

Abstract

Mesenchymal stromal cells (MSCs) are seen as an ideal source of cells to induce graft acceptance; however, some reports have shown that MSCs can be immunogenic rather than immunosuppressive. We speculate that the immunomodulatory effects of regulatory T cells (Tregs) can aid the maintenance of immunoregulatory functions of MSCs, and that a combinatorial approach to cell therapy can have synergistic immunomodulatory effects on allograft rejection. After preconditioning with Fludarabine, followed by total body irradiation and anti-asialo-GM-1(ASGM-1), tail skin grafts from C57BL/6 (H-2kb) mice were grafted onto the lateral thoracic wall of BALB/c (H-2kd) mice. Group A mice (control group, n = 9) did not receive any further treatment after preconditioning, whereas groups B and C (n = 9) received cell therapy with MSCs or Tregs, respectively, on days −1, +6 and +13 relative to the skin transplantation. Group D (n = 10) received cell therapy with MSCs and Tregs on days −1, +6 and +13. Cell suspensions were obtained from the spleens of five randomly chosen mice from each group on day +7, and the immunomodulatory effects of the cell therapy were evaluated by flow cytometry and real-time PCR. Our results show that allograft survival was significantly longer in group D compared to the control group (group A). Flow cytometric analysis and real-time PCR for splenocytes revealed that the Th2 subpopulation in group D increased significantly compared to the group B. Also, the expression of Foxp3 and STAT 5 increased significantly in group D compared to the conventional cell therapy groups (B and C). Taken together, these data suggest that a combined cell therapy approach with MSCs and Tregs has a synergistic effect on immunoregulatory function in vivo, and might provide a novel strategy for improving survival in allograft transplantation.

Immunomodulatory effects of OX40Ig gene-modified adipose tissue-derived mesenchymal stem cells on rat kidney transplantation

“…The upregulation of IL-10 and TGF-β is important for the differentiation and proliferation of Tregs. Tregs have very important immunoregulatory effects and play a significant role in the induction of immunotolerance or the maintenance of immunosuppressive activity (44). These data provide evidence that increased allograft survival following ADSCs OX40Ig administration, at least in part, occurs in association with the increased intragraft expression of genes associated with altered T cell differentiation, as well as a shift from a pro-inflammatory to an anti-inflammatory state.…”

Overcoming immunoregulatory plasticity of mesenchymal stem cells for accelerated clinical applications

“…In our group, we implemented the use of a combined cell therapy approach for the treatment of acute GVHD [53], induction of mixed chimerism following BMT [54], and prevention of allogeneic skin-graft rejection [55]. We observed that the combined cell therapy groups in all models showed enhanced survival and reduced clinicopathological symptoms.…”

Myeloid-Derived Suppressor Cells Therapy Enhance Immunoregulatory Properties in Acute Graft Versus Host Diseas with Combination of Regulatory T Cells

“…These data suggest that the combination of MDSCs and Tregs has potent immunoregulatory effects in mice and humans. Previous reports suggest that the combination of MSCs and Treg cell therapy have enhanced therapeutic e cacy in transplantation model [43][44][45]. However, the mechanism underlying cross talk between MSC and Treg remains unclear [46].…”