Mesenchymal Stem Cells and Co-stimulation Blockade Enhance Bone Marrow Engraftment and Induce Immunological Tolerance

Abstract

Background: Organ transplantation currently requires long-term immunosuppression. This is associated with multiple complications including infection, malignancy and other toxicities. Immunologic tolerance is considered the optimal solution to these limitations.

Objective: To develop a simple and non-toxic regimen to induce mixed chimerism and tolerance using mesenchymal stem cell (MSC) in a murine model.

Methods: Wild type C57BL6 (H2D^k) and Bal/C (H2D^d) mice were used as donors and recipients, respectively. We studied to achieve tolerance to skin grafts (SG) through mixed chimerism (MC) by simultaneous skin graft and non-myeloablative donor bone marrow transplantation (DBMT) +/– MSC. All recipients received rapamycin and CTLA-4 Ig without radiation.

Results: DBMT+MSC combined with co-stimulation blockage and rapamycin led to stable mixed chimerism, expansion of Tregs population and donor-specific skin graft tolerance. The flow cytometry analysis revealed that recipient mice developed 15%–85% chimerism. The skin allografts survived for a long time. Elimination of MSC failed to induce mixed chimerism and tolerance.

Conclusion: Our results demonstrate that donor-specific immune tolerance can be effectively induced by non-myeloablative DBMT-MSC combination without any additional cytoreductive treatment. This approach provides a promising and non-toxic allograft tolerance strategy.