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

Background: 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. Methods: 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 × 106 cells/time administered intravenously on days 7, 14, and 21). Results: 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-&bgr; and interleukin-10 levels. Conclusions: 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.

[1]  Y. Kuo,et al.  Prolongation of Composite Tissue Allotransplant Survival by Treatment with Bone Marrow Mesenchymal Stem Cells Is Correlated with T-Cell Regulation in a Swine Hind-Limb Model , 2011, Plastic and reconstructive surgery.

[2]  Ronald G. Tompkins,et al.  Mesenchymal Stem Cells: Mechanisms of Immunomodulation and Homing , 2010, Cell transplantation.

[3]  W. Morrison.  Face transplantation , 2009, ANZ journal of surgery.

[4]  Feng-Sheng Wang,et al.  Mesenchymal Stem Cells Prolong Composite Tissue Allotransplant Survival in a Swine Model , 2009, Transplantation.

[5]  Kuender D Yang,et al.  Alloantigen-pulsed host dendritic cells induce T-cell regulation and prolong allograft survival in a rat model of hindlimb allotransplantation. , 2009, The Journal of surgical research.

[6]  Manuel A. González,et al.  Human adipose-derived mesenchymal stem cells reduce inflammatory and T cell responses and induce regulatory T cells in vitro in rheumatoid arthritis , 2009, Annals of the rheumatic diseases.

[7]  Haiyang Xie,et al.  Immunosuppressive effects of rat mesenchymal stem cells: involvement of CD4+CD25+ regulatory T cells. , 2008, Hepatobiliary & pancreatic diseases international : HBPD INT.

[8]  J. Ryan,et al.  Cell contact, prostaglandin E2 and transforming growth factor beta 1 play non‐redundant roles in human mesenchymal stem cell induction of CD4+CD25Highforkhead box P3+ regulatory T cells , 2008, Clinical and experimental immunology.

[9]  M. Yarmush,et al.  Bone Marrow‐Derived Mesenchymal Stem Cells Ameliorate Autoimmune Enteropathy Independently of Regulatory T Cells , 2008, Stem cells.

[10]  A. Kirk,et al.  The Banff 2007 Working Classification of Skin‐Containing Composite Tissue Allograft Pathology , 2008, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[11]  Bindiya Patel,et al.  Adipose-derived stem cells: isolation, expansion and differentiation. , 2008, Methods.

[12]  P. Butler,et al.  Immunosuppression in an emerging field of plastic reconstructive surgery: composite tissue allotransplantation. , 2008, Journal of plastic, reconstructive & aesthetic surgery : JPRAS.

[13]  A. Sirigu,et al.  Outcomes 18 months after the first human partial face transplantation. , 2007, The New England journal of medicine.

[14]  R. Izadpanah,et al.  Biologic properties of mesenchymal stem cells derived from bone marrow and adipose tissue , 2006, Journal of cellular biochemistry.

[15]  M. Pittenger,et al.  Human mesenchymal stem cells modulate allogeneic immune cell responses. , 2005, Blood.

[16]  Roland Meisel,et al.  Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenase-mediated tryptophan degradation. , 2004, Blood.

[17]  M. Krampera,et al.  Bone marrow mesenchymal stem cells inhibit the response of naive and memory antigen-specific T cells to their cognate peptide. , 2003, Blood.

[18]  W. Lee,et al.  Composite tissue transplantation: more science and patience needed. , 2001, Plastic and Reconstructive Surgery.

[19]  M. Pittenger,et al.  Multilineage potential of adult human mesenchymal stem cells. , 1999, Science.

[20]  A. Weiland,et al.  Relative Antigenicity of Components of a Vascularized Limb Allograft , 1991, Plastic and reconstructive surgery.

[21]  A. Ghaderi,et al.  Adipose derived stem cells (ASCs) isolated from breast cancer tissue express IL-4, IL-10 and TGF-β1 and upregulate expression of regulatory molecules on T cells: do they protect breast cancer cells from the immune response? , 2011, Cellular immunology.

[22]  W P Cooney,et al.  Successful hand transplantation--one year follow-up. , 2001, The New England journal of medicine.

[23]  D. Mathes,et al.  Strategies for tolerance induction to composite tissue allografts , 2000, Microsurgery.

[24]  S. Gruber,et al.  Successful hand transplantation. One-year follow-up. Louisville Hand Transplant Team. , 2000, The New England journal of medicine.