title: Mesenchymal stem cells facilitate the induction of mixed hematopoietic chimerism and islet allograft tolerance without GVHD in the rat.
abstract: Induction of hematopoietic chimerism and subsequent donor-specific immune tolerance via bone marrow transplantation is an ideal approach for islet transplantation to treat type-1 diabetes. We examined the potential of mesenchymal stem cells (MSCs) in the induction of chimerism and islet allograft tolerance without the incidence of graft-versus-host disease (GVHD). Streptozotocin-diabetic rats received a conditioning regimen consisting of antilymphocyte serum and 5 Gy total body irradiation, followed by an intraportal co-infusion of allogeneic MSCs, bone marrow cells (BMCs) and islets. Although all the recipients rejected the islets initially, half of them developed stable mixed chimerism and donor-specific immune tolerance, shown by the engraftment of donor skin and second-set islet transplants and acute rejection of a third-party skin. The engraftment of the primary islet allografts with stable chimerism was achieved by the addition of a 2-week peritransplant administration of 15-deoxyspergualin (DSG). Without MSCs, none of the recipients treated with DSG developed chimerism or reversal of diabetes. GVHD was not observed in any of the recipients infused with MSCs (0/15), whereas it occurred in 4/11 recipients without MSCs. These results indicate a potential use of MSCs for induction of hematopoietic chimerism and subsequent immune tolerance in clinical islet transplantation.
authors.affiliation: Southern California Islet Cell Resource Center, Department of Diabetes, Endocrinology and Metabolism, Duarte, CA, USA. sitakura@coh.org
authors.forename: S
authors.initials: S
authors.lastname: Itakura
authors.forename: S
authors.initials: S
authors.lastname: Asari
authors.forename: J
authors.initials: J
authors.lastname: Rawson
authors.forename: T
authors.initials: T
authors.lastname: Ito
authors.forename: I
authors.initials: I
authors.lastname: Todorov
authors.forename: C-P
authors.initials: CP
authors.lastname: Liu
authors.forename: N
authors.initials: N
authors.lastname: Sasaki
authors.forename: F
authors.initials: F
authors.lastname: Kandeel
authors.forename: Y
authors.initials: Y
authors.lastname: Mullen
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation / Q000379:methods*; D002478:Cells, Cultured; D002678:Chimera; D003921:Diabetes Mellitus, Experimental / Q000601:surgery; D003922:Diabetes Mellitus, Type 1 / Q000628:therapy; D006084:Graft Rejection / Q000276:immunology / Q000473:pathology; D006086:Graft vs Host Disease / Q000276:immunology / Q000517:prevention & control*; D018380:Hematopoietic Stem Cell Transplantation; D007108:Immune Tolerance / Q000276:immunology*; D007165:Immunosuppression Therapy; D016381:Islets of Langerhans Transplantation / Q000276:immunology* / Q000473:pathology; D007694:Killer Cells, Natural / Q000276:immunology / Q000473:pathology; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D023001:Transplantation Tolerance / Q000276:immunology; D014184:Transplantation, Homologous / Q000276:immunology