title: Cyclosporine immunosuppression does not prevent the production of donor-specific antibody capable of mediating allograft vasculopathy.
abstract: BACKGROUND
  Late cardiac graft rejection, primarily mediated by allograft vasculopathy (AV), remains a major limitation to cardiac transplantation, even in the face of significant calcineurin inhibitor (CNI) immunosuppression. The role played by alloantibody in AV is unclear. Evidence that CNI immunosuppression suppresses CD4(+) T-cell function would suggest that antibody production and effector function would be severely limited in CNI-treated patients. In this study we examine the capacity of CNI-treated animals to develop effective alloantibody that can mediate AV.
  
  
  METHODS
  Wild-type (WT) B6 mice were alloimmunized using donor splenocytes or a fully major histocompatibility complex-mismatched allogeneic abdominal aortic graft in the presence of CNI immunosuppression (30 or 50 mg/kg/day cyclosporine A). Anti-serum was harvested and tested using complement-dependent in vitro cytotoxicity assays. Anti-serum was passively transferred to immunodeficient RAG1(-/-) recipients of allogeneic grafts. C4d deposition was quantified in the allografts from WT recipients.
  
  
  RESULTS
  CNI immunosuppression did not prevent the development of alloantibody in response to either immunization method (p < 0.05). Passive transfer of anti-serum generated AV lesions in immunodeficient graft recipients and mediated complement-dependent destruction of donor cells (p < 0.05). C4d deposition was localized to the media of grafts of CNI treated animals.
  
  
  CONCLUSIONS
  CNI therapy does not prevent the production of alloantibody with the capacity to mediate AV. C4d deposition in the media suggests a role for medial smooth muscle cell loss in antibody-mediated AV lesion development in our model.
authors.affiliation: Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Gareau
authors.forename: Bjorn
authors.initials: B
authors.lastname: Nashan
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Hirsch
authors.forename: Timothy D G
authors.initials: TD
authors.lastname: Lee
mesh_terms: D000818:Animals; D000918:Antibody Specificity / Q000276:immunology*; D065095:Calcineurin Inhibitors; D016572:Cyclosporine / Q000627:therapeutic use*; D006084:Graft Rejection / Q000209:etiology / Q000276:immunology; D016027:Heart Transplantation; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007518:Isoantibodies / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D013601:T-Lymphocytes / Q000378:metabolism; D014019:Tissue Donors; D014184:Transplantation, Homologous; D014652:Vascular Diseases / Q000150:complications / Q000276:immunology*
chemical_list: D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D007518:Isoantibodies; D016572:Cyclosporine