Abstract
Mesenchymal stem cells (MSCs) are suggested to be immune modulators because of their therapeutic potential in transplantation. In the present study, we evaluated the therapeutic potential of autologous MSCs for preventing graft rejection after allogeneic rat islet transplantation. We assessed the ability of MSCs to elicit an antiproliferative response in alloreactive lymphocytes and tested the immunosuppressive effect of MSCs in allogeneic islet transplantation. In islet allotransplantation, injection of autologous MSCs or a subtherapeutic dose of cyclosporine A (CsA; 5 mg/kg) alone did not prolong allograft survival. However, graft survival was attained for >100 d in 33% of autologous MSC-plus-CsA-treated recipients, indicating that graft acceptance was achieved in a subgroup of allograft recipients. Splenocytes from autologous MSC-plus-CsA-treated rats exhibited a reduced mixed lymphocyte reaction (MLR)-proliferative response to donor stimulators and increased interleukin (IL)-10 release. Interestingly, after excluding host CD11b(+) cells, splenic T cells from autologous MSC-plus-CsA-treated rats did not produce IL-10 or did not inhibit proliferative responses under the same conditions. The use of autologous MSC-plus-CsA downregulated immune responses, inducing donor-specific T-cell hyporesponsiveness by reducing the production of proinflammatory cytokines and inducing antiinflammatory cytokine production, especially that of IL-10, during the early posttransplantation period. T-regulatory cells made a contribution at a later phase. In conclusion, the combined use of autologous MSCs and low-dose CsA exerted a synergistic immunosuppressive effect in an islet allograft model, suggesting a role for autologous MSCs as an immune modulator.
Highlights
Type 1 diabetes is an autoimmune disease caused by destruction of insulinproducing pancreatic islet cells
We further found that addition of Mesenchymal stem cells (MSCs) to mixed lymphocyte reaction (MLR) inhibited IL-2 and IFN-γ production while increasing the levels of IL-10, suggesting that IL-10 is important in mediating the suppressive capacity of MSCs (Figure 2C)
We found that in grafted livers from the allo–MSCplus-cyclosporine A (CsA) group, the expression of IL-2, IFN-γ, IL-4 and IL-10 was comparable to other groups at 20 days after transplantation
Summary
Type 1 diabetes is an autoimmune disease caused by destruction of insulinproducing pancreatic islet cells. Islet transplantation is considered a less effective treatment modality for Type 1 diabetes than pancreas transplantation, especially from the viewpoint of long-term graft survival. The islet rejection process is characterized by rapid infiltration of immune cells, followed by antigen-specific T-cell responses. On the basis of their capacity to modulate immune responses and to promote tissue repair in experimental models, MSCs have been proposed as a treatment for autoimmune diseases, such as diabetes, rheumatoid arthritis, systemic lupus erythematosus and multiple sclerosis. The use of MSCs to prevent rejection of allogeneic grafts is still mostly limited to animal models, and the results obtained to date are conflicting. We evaluated the therapeutic potential of autologous MSCs for prevention of graft rejection after allogeneic islet transplantation. We evaluated the expression profiles of pro- and antiinflammatory cytokine genes in the grafted site, serum cytokine levels, immune responses in splenocytes of recipients after allostimulation and the frequency of T-regulatory cells (Tregs) in secondary
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