Modulation of Immune Response and T-Cell Regulation by Donor Adipose-Derived Stem Cells in a Rodent Hind-Limb Allotransplant Model

Abstract

In this study, the authors investigated whether donor adipose-derived stem cells have immunomodulatory effects, such as regulation of T cells, modulation of related cytokines, and prolongation of composite tissue allotransplantation survival, in a rodent hind-limb model. Adipose-derived stem cells were obtained from donor adipose tissue and co-cultured with CD3 T cells from allogenic splenocytes for in vitro studies. Orthotopic hind-limb allotransplants were performed from Brown Norway to Lewis rats (day 0). Group 1 (control group) did not receive any treatment. Group 2 received cyclosporin A on days 0 to 20. Group 3 received antilymphocyte serum (day -4 and day 1) and cyclosporin A (days 0 to 20). Group 4 received cyclosporin A (days 0 to 20), antilymphocyte serum (day -4 and day 1), and adipose-derived stem cells (2 × 10 cells/time administered intravenously on days 7, 14, and 21). Adipose-derived stem cells exert immunomodulatory effects including suppressing T-cell proliferation and increasing CD4/CD25/Foxp3 regulatory T cells in vitro. The in vivo study revealed that, compared with untreated control, rats administered adipose-derived stem cells along with transient antilymphocyte serum and cyclosporin A treatment had significantly prolonged allotransplant survival (p < 0.001), decreased allotissue rejection, significantly elevated donor cell chimerism, and increased CD4/CD25/Foxp3 regulatory T cells in peripheral blood and alloskin tissue with up-regulation of transforming growth factor-β and interleukin-10 levels. In combination with transient immunosuppression, adipose-derived stem cells modulate the immune system and significantly prolong allotransplant survival. The underlying mechanisms include changes in antiinflammatory cytokine expression and T-cell functions.