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.
Highlights
Composite tissue allotransplantation (CTA), in which composite tissue consisting of skin, muscle and bone is transferred from one person to another, has successfully been used to treat tissue loss resulting from trauma, tumors, or congenital deformity
One strategy currently being considered is the use of toleranceinducing cells, such as mesenchymal stromal cells (MSCs) and regulatory T cells (Tregs), because they can reduce the side effects caused by traditional immunosuppressants [9,10,11,12]
It has been shown that donor MSCs are able to inhibit T-cell proliferation in a mixed lymphocyte culture, preventing graft-versus-host disease (GVHD) as a result of a bone marrow transplant (BMT), and prolonging skin allograft survival in baboons [16,17,18]
Summary
Composite tissue allotransplantation (CTA), in which composite tissue consisting of skin, muscle and bone is transferred from one person to another, has successfully been used to treat tissue loss resulting from trauma, tumors, or congenital deformity. The first successful human hand transplant was performed in 1998, and the first successful partial face allotransplant was performed in 2005 [1,2]. Nonspecific immunosuppressive drugs such as tacrolimus, mycophenolate mofetil and steroids have been used in patients receiving CTA, as in solid organ transplantation, with excellent results [1,3,4]. It has been shown that donor MSCs are able to inhibit T-cell proliferation in a mixed lymphocyte culture, preventing graft-versus-host disease (GVHD) as a result of a bone marrow transplant (BMT), and prolonging skin allograft survival in baboons [16,17,18]
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