title: Regulation of anti-HLA antibody-dependent natural killer cell activation by immunosuppressive agents.
abstract: BACKGROUND
  It was demonstrated that human natural killer (NK) cells, via antibody-dependent cellular cytotoxicity (ADCC)-like mechanism, increase IFNγ production after exposure to alloantigens. This finding was associated with an increased risk for antibody-mediated rejection (ABMR). Although the effects of various immunosuppressive drugs on T cells and B cells have been extensively studied, their effects on NK cells are less clear. This study reports the effect of immunosuppressive agents on antibody-mediated NK cell activation in vitro.
  
  
  METHODS
  Whole blood from normal individuals was incubated with irradiated peripheral blood mononuclear cells (PBMCs) pretreated with anti-HLA antibody+ sera (in vitro ADCC), with or without immunosuppressive agents. The %IFNγ+ and CD107a+ (degranulation marker) in CD56+ NK cells were enumerated by flow cytometry.
  
  
  RESULTS
  Cyclosporine A and tacrolimus significantly reduced IFNγ production in a dose-dependent manner (53%-83%), but showed minimal effect on degranulation (20%). Prednisone significantly reduced both IFNγ production and degranulation (50%-66% reduction at maximum therapeutic levels). Calcineurin inhibitors (CNIs) in combination with prednisone additively suppressed IFNγ production and degranulation. The effect of sirolimus or mycophenolate mofetil on NK cells was minimal.
  
  
  CONCLUSIONS
  These results suggest that potent suppressive effects of CNIs and prednisone on antibody-mediated NK cell activation may contribute to the reduction of ADCC in sensitized patients and possibly reduce the risk for ADCC-mediated ABMR. These further underscore the importance of medication compliance in prevention of ABMR and possibly chronic rejection, and suggest that ADCC-mediated injury may increase in strategies aimed at CNI or steroid minimization or avoidance.
authors.affiliation: 1 Transplant Immunology Laboratory, Comprehensive Transplant Center, Cedars-Sinai Medical Center/UCLA School of Medicine, Los Angeles, CA. 2 Comprehensive Transplant Center, Cedars-Sinai Medical Center/UCLA School of Medicine, Los Angeles, CA. 3 Biostatistics Core, Research Institute, General Clinical Research Center, Cardiothoracic Surgery, Cedars-Sinai Medical Center, Los Angeles, CA. 4 Address correspondence to: Bong-Ha Shin, Ph.D., Transplant Immunology Laboratory, SSB111, Comprehensive Transplant Center, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, CA 90048.
authors.forename: Bong-Ha
authors.initials: BH
authors.lastname: Shin
authors.forename: Shili
authors.initials: S
authors.lastname: Ge
authors.forename: James
authors.initials: J
authors.lastname: Mirocha
authors.forename: Artur
authors.initials: A
authors.lastname: Karasyov
authors.forename: Ashley
authors.initials: A
authors.lastname: Vo
authors.forename: Stanley C
authors.initials: SC
authors.lastname: Jordan
authors.forename: Mieko
authors.initials: M
authors.lastname: Toyoda
mesh_terms: D000906:Antibodies / Q000737:chemistry*; D000920:Antibody-Dependent Cell Cytotoxicity; D019002:CD56 Antigen / Q000378:metabolism; D065095:Calcineurin Inhibitors; D016572:Cyclosporine / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D006680:HLA Antigens / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D007165:Immunosuppression Therapy / Q000379:methods*; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007249:Inflammation; D007371:Interferon-gamma / Q000378:metabolism; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D052118:Lysosomal-Associated Membrane Protein 1 / Q000378:metabolism; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000627:therapeutic use; D012306:Risk; D020123:Sirolimus / Q000627:therapeutic use; D016559:Tacrolimus / Q000627:therapeutic use
chemical_list: D000906:Antibodies; D019002:CD56 Antigen; D065095:Calcineurin Inhibitors; D006680:HLA Antigens; D007166:Immunosuppressive Agents; D052118:Lysosomal-Associated Membrane Protein 1; D007371:Interferon-gamma; D016572:Cyclosporine; D009173:Mycophenolic Acid; D020123:Sirolimus; D016559:Tacrolimus