Mesenchymal stem cells enhance the induction of mixed chimerism and tolerance to rat hind-limb allografts after bone marrow transplantation.

Background: Mixed hematopoietic chimerism via bone marrow transplantation has been shown to induce donor specific tolerance to solid organ allografts, but graft versus host disease (GVHD) remains to be a risk. Composite tissue allografts may need a higher percentage of donor chimerism compared with less immunogenic solid organ allografts. In this study, we investigated the potential of mesenchymal stem cells (MSCs) in the induction of stable and high level chimerism and subsequent donor-specific tolerance to composite tissue allograft without the incidence of graft versus host disease (GVHD).

Methods: Fully mismatched, 4- to 8-wk-old Brown Norway (RT1(n)) and Lewis (RT1(1)) rats were used as cell or hind-limb donors and recipients, respectively. Recipients received a conditioning regimen consisting of antilymphocyte serum, standard immunosuppressive therapy (rapamycin: 0.2 mg/kg/d; days 0 approximately 130) and 3 Gy total body irradiation, followed by an intraportal co-infusion of allogeneic MSCs and bone marrow cells (day 0); then performing hind-limb allotransplants (30 d after BMT); 100 d after hind-limb transplantations, immunosuppressive therapy was stopped and to observe the survival time of the hind-limb allografts.

Results: When co-infusion of allogeneic MSCs was administered, 14/15 recipients developed stable and high level chimerism. Subsequently, in the donor specific group, the survival time of hind-limb allografts without RAPA were remarkably prolonged compared with other groups. The results of the histopathological evaluation of skin biopsy and mixed lymphocyte cultures confirmed this operational donor specific tolerance. Without MSCs, only 2/7 of the recipients developed stable chimerism, but GVHD occurred in both of them, and the level of the chimerism was much lower. On the other hand, GVHD was not observed in any of the recipients infused with MSCs (0/15).

Conclusion: This study indicates a potential use of MSCs for induction of stable and high level mixed hematopoietic chimerism and subsequent donor specific tolerance in clinical composite tissue allotransplantation.