title: Reduction of transplant arteriosclerosis after treatment with mycophenolate mofetil and ganciclovir in a mouse aortic allograft model.
abstract: OBJECTIVE
  Transplant arteriosclerosis is a major obstacle for long-term allograft survival in heart transplant. The aim of this study was to investigate potential synergistic effects of combined treatment with mycophenolate mofetil and ganciclovir on the development of transplant arteriosclerosis, presence of regulatory T cells, and expression of donor specific alloantibodies.
  
  
  METHODS
  Donor aortas from C57BL/6 (H2b) mice that were fully mismatched to the major histocompatibility complex were transplanted into CBA (H2k) mouse recipients. Groups of mice received mycophenolate mofetil (100 or 300 mg/kg, oral), ganciclovir (10 or 72 mg/kg, intraperitoneal), or a mycophenolate mofetil and ganciclovir combination. Grafts were analyzed by histology and morphometry on day 30 after transplant. Numbers of regulatory T cells and donor-specific alloantibodies were examined by fluorescence-activated cell sorting analysis of splenic tissue and peripheral blood.
  
  
  RESULTS
  Mycophenolate mofetil (100 mg/kg) and ganciclovir (10 mg/kg and 72 mg/kg) did not show effects on transplant arteriosclerosis formation or alloantibody production. However, groups treated with mycophenolate mofetil (300 mg/kg) or a low- or high-dose mycophenolate mofetil and ganciclovir combination had significantly reduced transplant arteriosclerosis and alloantibody levels. Expression of regulatory T cells within the spleen was similar between all experimental groups and untreated controls.
  
  
  CONCLUSIONS
  The combination of mycophenolate mofetil and ganciclovir significantly reduced the development of transplant arteriosclerosis in a mouse abdominal aortic allograft model. This effect may be a result of decreased alloantibody production.
authors.affiliation: Department of Cardiac Surgery, Friedrich Alexander University Erlangen-Nürnberg, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Hoffmann
authors.forename: Martin
authors.initials: M
authors.lastname: Böhm
authors.forename: Silke
authors.initials: S
authors.lastname: Abele-Ohl
authors.forename: Martina
authors.initials: M
authors.lastname: Ramsperger-Gleixner
authors.forename: Bernd M
authors.initials: BM
authors.lastname: Spriewald
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Zinser
authors.forename: Alexander
authors.initials: A
authors.lastname: Steinkasserer
authors.forename: Michael
authors.initials: M
authors.lastname: Weyand
authors.forename: Stephan M
authors.initials: SM
authors.lastname: Ensminger
mesh_terms: D000818:Animals; D000917:Antibody Formation / Q000187:drug effects; D001011:Aorta / Q000637:transplantation*; D001012:Aorta, Abdominal / Q000637:transplantation; D001161:Arteriosclerosis / Q000517:prevention & control*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D015774:Ganciclovir / Q000008:administration & dosage*; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D007518:Isoantibodies / Q000032:analysis; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives*; D011183:Postoperative Complications / Q000517:prevention & control; D013154:Spleen / Q000166:cytology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology; D014184:Transplantation, Homologous
chemical_list: D007166:Immunosuppressive Agents; D007518:Isoantibodies; D009173:Mycophenolic Acid; D015774:Ganciclovir