Adipose-derived Stem Cell-Based Immunomodulatory Therapy in a Translational Porcine Limb Transplant Model
Deokyeol Kim, MD, Matthias Waldner, MD, Wensheng Zhang, MD, Mario Solari, MD, Kia Washington, MD, Kacey Marra, PhD, J. Peter Rubin, MD.
Department of Plastic Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
PURPOSE: Mesenchymal stem cells deriving from bone marrow and adipose tissue have immunomodulatory effects and low immunogenicity. Cell therapy using donor-derived bone marrow cells is already being used clinically and has reduced the burden of immunosuppressive drugs in vascularized composite allotransplantation (VCA) patients. However, the quantity of donor-derived bone marrow cells that can be effectively harvested from an individual donor is limited. Adipose-derived stem cells (ASCs) represent another clinically useful source of cell therapy for allotransplantation. This study was designed to investigate whether ASCs treatment could prolong graft survival in a porcine large animal model.
METHODS: Full-major histocompatibility complex (MHC) mismatched heterotopic hind-limb transplantations were performed in MGH mini-swine. Animals receiving no therapy and animals treated with tacrolimus for the initial 30 days served as control and standard therapy group, respectively. Experimental animals were treated with a standard immunosuppressive protocol including tacrolimus for 30 days, followed by ASC therapy (donor-derived ASCs [1.0x10^6 cells/kg] administered intravenously in recipients at post-operative day 7). Allograft survival was compared across the different treatment protocols.
RESULTS: Six allogenic hind limb transplantations in the mini-swine were performed in three groups. The control group reached Banff grade 4 acute rejection by an average of 7.5 days after transplantation. Allografts treated with ASCs demonstrated grade 4 rejection on day 119 and demonstrated rejection-free survival over 200 days postoperatively, which was longer than the standard therapy group. The long-term survivor of the ASCs therapy group showed donor-specific unresponsiveness and regulatory T cells upregulation.
CONCLUSION: Early results of ongoing in vivo experimentation show promising results of ASC therapy in prolonging acute rejection-free VCA survival across a full MHC mismatch. Achieved immune tolerance by cellular immunomodulation is considered to prolong allograft survival.
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