Use of donor bone marrow mesenchymal stem cells for treatment of skin allograft rejection in a preclinical rat model

Abstract

Recent studies indicate that mesenchymal stem cells (MSC) exhibit a degree of immune privilege due to their ability to suppress T cell mediated responses causing tissue rejection; however, the impact of allogeneic MSC in the setting of organ transplantation has been poorly investigated so far. The aim of our study was to evaluate the eVect of intravenous donor MSC infusion for clinical tolerance induction in allogeneic skin graft transplantations in rats. MSC were isolated from Wistar rats and administered in Sprague-Dawley rats receiving Wistar skin graft with or without cyclosporine A (CsA). Graft biopsies were performed at day 10 post transplantation in all experimental groups for histological and gene expression studies. Intravenous infusion with donor MSC in CsA-treated transplanted rats resulted in prolongation of skin allograft survival compared to control animals. Unexpectedly, donor MSC infusion in immunocompetent rats resulted in a faster rejection as compared to control group. Cytokine expression analysis at the site of skin graft showed that CsA treatment signiWcantly decreased pro-inXammatory cytokines IFN-and IL-2 and reduced TNF-gene expression; however, the level of TNF-is high in MSC-treated and not immunosuppressed rats. Results of our study in a rat tissue transplantation model demonstrated a possible immunogenic role for donor (allogeneic) MSC, conWrming the need of adequate preclinical experimentation before clinical use.

Immunomodulatory Effects of Different Cellular Therapies of Bone Marrow Origin on Chimerism Induction and Maintenance Across MHC Barriers in a Face Allotransplantation Model

“…In this study we have relied on the immunomodulatory properties of MSC. MSC decrease T-cell activation in vivo, probably by inhibiting dendritic cell maturation and antigen-presenting function, as well as proliferation and (Bartholomew et al 2002) or shorten (Inoue et al 2006;Sbano et al 2008) allograft survival. Finally, MSCs inhibit the afferent phase of alloreactivity, but not the cytotoxic effects of the activated T cells (Rasmusson et al 2003).…”

New advances in the mesenchymal stem cells therapy against skin flaps necrosis

“…The co-infusion of MSCs with unmodified donor bone marrow limited the toxicity of allogeneic bone marrow transplantation, treated graft vs host disease (GVHD), enhanced mixed chimerism and improved vascularized skin graft survival [35] . The high level of TNF-α also demonstrated a possible immunogenic role for donor (allogeneic) MSCs against skin allograft rejection [36] . Lee et al [37] suggested that ADSCs and their secretome had the potential to induce immunologic tolerance in fullthickness skin allotransplantation model.…”

Mesenchymal stem cells for kidney transplantation

“…There is evidence that allogeneic MSCs can trigger an anti-donor immune response resulting in accelerated allograft rejection [65][66][67] . The co-administration of allogeneic MSC with immunosuppressive drugs however showed better outcome of the allograft compared to MSC monotherapy [63,64,[70][71][72] . Therefore, the synergistic effects of allogeneic MSC with immunosuppressive drugs need to be taken into consideration in MSC therapy.…”

“…Nevertheless, issues pertaining to the immunogenicity of allogeneic or third-party derived MSCs has not been substantially addressed in vivo and have not been addressed in large animal models. There are preclinical studies demonstrating that allogeneic MSC monotherapy alone failed to prevent allograft rejection [60][61][62][63][64][65][66][67][68][69] . Studies reporting on the benefits of allogeneic MSCs have also shown short term prolongation of graft survival [64] .…”