title: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Surgery, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: B
authors.initials: B
authors.lastname: Rajeshkumar
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: P
authors.initials: P
authors.lastname: Agrawal
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Rashighi
authors.affiliation: Division of Organ Transplantation, Department of Surgery, Alpert Medical School of Brown University, Providence, RI, USA.
authors.forename: R F
authors.initials: RF
authors.lastname: Saidi
keywords: Immunosuppression; Infection; Organ transplantation