title: Multipotent mesenchymal stromal cells synergize with costimulation blockade in the inhibition of immune responses and the induction of Foxp3+ regulatory T cells.
abstract: Multipotent mesenchymal stromal cell (MSC) therapy and costimulation blockade are two immunomodulatory strategies being developed concomitantly for the treatment of immunological diseases. Both of these strategies have the capacity to inhibit immune responses and induce regulatory T cells; however, their ability to synergize remains largely unexplored. In order to study this, MSCs from C57BL/6 (H2b) mice were infused together with fully major histocompatibility complex-mismatched Balb/c (H2d) allogeneic islets into the portal vein of diabetic C57BL/6 (H2b) mice, which were subsequently treated with costimulation blockade for the first 10 days after transplantation. Mice receiving both recipient-type MSCs, CTLA4Ig, and anti-CD40L demonstrated indefinite graft acceptance, just as did most of the recipients receiving MSCs and CTLA4Ig. Recipients of MSCs only rejected their grafts, and fewer than one half of the recipients treated with costimulation blockade alone achieved permanent engraftment. The livers of the recipients treated with MSCs plus costimulation blockade contained large numbers of islets surrounded by Foxp3+ regulatory T cells. These recipients showed reduced antidonor IgG levels and a glucose tolerance similar to that of naïve nondiabetic mice. Intrahepatic lymphocytes and splenocytes from these recipients displayed reduced proliferation and interferon-γ production when re-exposed to donor antigen. MSCs in the presence of costimulation blockade prevented dendritic cell maturation, inhibited T cell proliferation, increased Foxp3+ regulatory T cell numbers, and increased indoleamine 2,3-dioxygenase activity. These results indicate that MSC infusion and costimulation blockade have complementary immune-modulating effects that can be used for a broad number of applications in transplantation, autoimmunity, and regenerative medicine.
authors.affiliation: Division of Transplantation Surgery, Karolinska Institutet, CLINTEC, Stockholm, Sweden; Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Department of Clinical Chemistry and Transfusion Medicine, The Sahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden; Department of Cardiothoracic Surgery and Anesthesiology, Karolinksa University Hospital, Stockholm, Sweden tohru.takahashi@ki.se takmkz79@yahoo.co.jp.
authors.forename: Tohru
authors.initials: T
authors.lastname: Takahashi
authors.affiliation: Division of Transplantation Surgery, Karolinska Institutet, CLINTEC, Stockholm, Sweden; Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Department of Clinical Chemistry and Transfusion Medicine, The Sahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden; Department of Cardiothoracic Surgery and Anesthesiology, Karolinksa University Hospital, Stockholm, Sweden.
authors.forename: Annika
authors.initials: A
authors.lastname: Tibell
authors.affiliation: Division of Transplantation Surgery, Karolinska Institutet, CLINTEC, Stockholm, Sweden; Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Department of Clinical Chemistry and Transfusion Medicine, The Sahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden; Department of Cardiothoracic Surgery and Anesthesiology, Karolinksa University Hospital, Stockholm, Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: Ljung
authors.affiliation: Division of Transplantation Surgery, Karolinska Institutet, CLINTEC, Stockholm, Sweden; Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Department of Clinical Chemistry and Transfusion Medicine, The Sahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden; Department of Cardiothoracic Surgery and Anesthesiology, Karolinksa University Hospital, Stockholm, Sweden.
authors.forename: Yu
authors.initials: Y
authors.lastname: Saito
authors.affiliation: Division of Transplantation Surgery, Karolinska Institutet, CLINTEC, Stockholm, Sweden; Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Department of Clinical Chemistry and Transfusion Medicine, The Sahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden; Department of Cardiothoracic Surgery and Anesthesiology, Karolinksa University Hospital, Stockholm, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Gronlund
authors.affiliation: Division of Transplantation Surgery, Karolinska Institutet, CLINTEC, Stockholm, Sweden; Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Department of Clinical Chemistry and Transfusion Medicine, The Sahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden; Department of Cardiothoracic Surgery and Anesthesiology, Karolinksa University Hospital, Stockholm, Sweden.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Osterholm
authors.affiliation: Division of Transplantation Surgery, Karolinska Institutet, CLINTEC, Stockholm, Sweden; Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Department of Clinical Chemistry and Transfusion Medicine, The Sahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden; Department of Cardiothoracic Surgery and Anesthesiology, Karolinksa University Hospital, Stockholm, Sweden.
authors.forename: Jan
authors.initials: J
authors.lastname: Holgersson
authors.affiliation: Division of Transplantation Surgery, Karolinska Institutet, CLINTEC, Stockholm, Sweden; Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Department of Clinical Chemistry and Transfusion Medicine, The Sahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden; Department of Cardiothoracic Surgery and Anesthesiology, Karolinksa University Hospital, Stockholm, Sweden.
authors.forename: Torbjörn
authors.initials: T
authors.lastname: Lundgren
authors.affiliation: Division of Transplantation Surgery, Karolinska Institutet, CLINTEC, Stockholm, Sweden; Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Department of Clinical Chemistry and Transfusion Medicine, The Sahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden; Department of Cardiothoracic Surgery and Anesthesiology, Karolinksa University Hospital, Stockholm, Sweden.
authors.forename: Bo-Göran
authors.initials: BG
authors.lastname: Ericzon
authors.affiliation: Division of Transplantation Surgery, Karolinska Institutet, CLINTEC, Stockholm, Sweden; Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Department of Clinical Chemistry and Transfusion Medicine, The Sahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden; Department of Cardiothoracic Surgery and Anesthesiology, Karolinksa University Hospital, Stockholm, Sweden.
authors.forename: Matthias
authors.initials: M
authors.lastname: Corbascio
authors.affiliation: Division of Transplantation Surgery, Karolinska Institutet, CLINTEC, Stockholm, Sweden; Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Department of Clinical Chemistry and Transfusion Medicine, The Sahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden; Department of Cardiothoracic Surgery and Anesthesiology, Karolinksa University Hospital, Stockholm, Sweden.
authors.forename: Makiko
authors.initials: M
authors.lastname: Kumagai-Braesch
mesh_terms: D064591:Allografts; D000818:Animals; D049109:Cell Proliferation; D003921:Diabetes Mellitus, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy; D051858:Forkhead Transcription Factors / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000276:immunology; D050417:Insulin-Secreting Cells / Q000276:immunology / Q000637:transplantation; D007371:Interferon-gamma / Q000276:immunology; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D039902:Multipotent Stem Cells / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D007074:Immunoglobulin G; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007371:Interferon-gamma
keywords: Anti-CD40L; CTLA4Ig; Costimulation blockade; Foxp3+ regulatory T cell; Mesenchymal stem cells; Rejection