title: Requirement of B7-H1 in mesenchymal stem cells for immune tolerance to cardiac allografts in combination therapy with rapamycin.
abstract: BACKGROUND
  The potential of mesenchymal stem cells (MSCs) for immunosuppression has been tested in transplantation, but its mechanisms are not fully understood. This study investigated the role of MSC-expressing B7-H1 in the induction of immune tolerance to cardiac allografts by the combination therapy of MSCs and rapamycin (RAPA).
  
  
  METHODS
  The anti-alloimmunity of donor MSCs in the presence or absence of RAPA was examined in both mouse cardiac allograft model (C57BL/6 to BALB/c mice) and a variety of cultured immune cells. Immunohistochemical staining was used for the measurement of intragraft antibody deposition, and fluorescence-activated cell sorting (FACS) for the determination of serum alloantibodies and leukocyte phenotypes.
  
  
  RESULTS
  B7-H1 expression in cultured MSCs was up-regulated following IFN-γ stimulation. In transplant recipients, combination therapy of MSCs and RAPA induced immune tolerance to allografts, but blockade of B7-H1 on MSCs with monoclonal antibody abrogated the combination therapy-induced immune tolerance as heart allografts were rejected. The negative effect of MSC-expressing B7-H1 neutralization on graft survival was correlated with a reduction of regulatory immune cells (CD4(+)CD25(+)Foxp3(+) T cells, tolerogenic dendritic cells and IL-4(high)IL-10(High)CD83(low) B cells), and also with an increase in alloantibody (IgG and IgM) levels both inside the grafts and in the circulation as compared with un-neutralized controls. In vitro MSC-mediated suppression of antibody production and B cell proliferation depended on B7-H1 function and cell contact between CD19(+) B cells and MSCs.
  
  
  CONCLUSIONS
  These data suggest that MSC-expressing B7-H1 mediates the immune tolerance to cardiac allografts in recipients receiving MSC and RAPA combination therapy.
authors: Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China; Tianjin General Surgery Institute, Tianjin, China. Electronic address: hwangca272@gmail.com.
authors: Hao
authors: H
authors: Wang
authors: Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China.
authors: Feng
authors: F
authors: Qi
authors: Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China.
authors: Xiangchen
authors: X
authors: Dai
authors: Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China.
authors: Weijun
authors: W
authors: Tian
authors: Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China; Tianjin General Surgery Institute, Tianjin, China.
authors: Tong
authors: T
authors: Liu
authors: Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China.
authors: Hongqiu
authors: H
authors: Han
authors: Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China.
authors: Bai
authors: B
authors: Zhang
authors: Tianjin General Surgery Institute, Tianjin, China.
authors: Hongyue
authors: H
authors: Li
authors: Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China.
authors: Zhixiang
authors: Z
authors: Zhang
authors: Department of Urologic Sciences, The University of British Columbia, Vancouver, BC, Canada; Immunity and Infection Research Centre, Vancouver Coastal Health Research Institute, Vancouver, British Columbia; Canada. Electronic address: caigan@mail.ubc.ca.
authors: Caigan
authors: C
authors: Du
mesh_terms: D064591:Allografts; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001402:B-Lymphocytes / Q000276:immunology; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D001854:Bone Marrow Cells / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002450:Cell Communication / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D005434:Flow Cytometry; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology; D016027:Heart Transplantation; D007074:Immunoglobulin G / Q000097:blood; D007075:Immunoglobulin M / Q000097:blood; D007155:Immunologic Factors / Q000494:pharmacology; D007165:Immunosuppression Therapy / Q000379:methods; D007371:Interferon-gamma / Q000494:pharmacology; D007518:Isoantibodies / Q000097:blood; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D020123:Sirolimus / Q000627:therapeutic use*; D023001:Transplantation Tolerance / Q000187:drug effects*
chemical_list: D000911:Antibodies, Monoclonal; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D007155:Immunologic Factors; D007518:Isoantibodies; D007371:Interferon-gamma; D020123:Sirolimus
keywords: B7-H1; Heart transplant; Immunosuppression; Mesenchymal stem cell; Rapamycin