title: Delayed therapy with clopidogrel and everolimus prevents progression of transplant arteriosclerosis and impairs humoral alloimmunity in murine aortic allografts.
abstract: OBJECTIVE
  It was previously shown that the combination of clopidogrel and everolimus reduced the development of transplant arteriosclerosis. The aim of this study was to investigate whether delayed onset of treatment, similar to the clinical situation after heart transplantation, inhibits progression of transplant arteriosclerosis.
  
  
  METHODS
  Fully allogeneic C57BL/6 (H2-b) donor aortas were transplanted into CBA.J (H2-k) recipients treated with clopidogrel and everolimus alone or in combination starting on Days 1, 7 or 14. Grafts were analysed by histology and alloantibodies were detected by fluorescence activated cell sorting after transplantation.
  
  
  RESULTS
  Delayed platelet inhibition with clopidogrel reduced the development of transplant arteriosclerosis [neointima formation (Day 14): 50±4 vs 84±9% (control)]. The combination of clopidogrel and everolimus almost abolished formation of transplant arteriosclerosis when therapy was started on Day 1 [neointima formation (Day 1): 14±5 vs 84±9% (control)] and also showed a remarkable reduction in both delayed treatment groups [neointima formation (Day 7): 24±7 vs 84±9% (control); neointima formation (Day 14): 28±11 vs 84±9% (control)]. Platelet inhibition alone and in combination with everolimus resulted in reduced alloantibody production.
  
  
  CONCLUSIONS
  These results demonstrate that delayed treatment with clopidogrel and everolimus-representative of a clinical setting-prevents the progression of transplant arteriosclerosis and impairs humoral immunity in this experimental model.
authors.affiliation: Department of Cardiac Surgery, Friedrich-Alexander University, Erlangen-Nürnberg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Heim
authors.affiliation: Department of Cardiac Surgery, Friedrich-Alexander University, Erlangen-Nürnberg, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Eckl
authors.affiliation: Department of Cardiac Surgery, Friedrich-Alexander University, Erlangen-Nürnberg, Germany.
authors.forename: Raimund
authors.initials: R
authors.lastname: Preidl
authors.affiliation: Department of Cardiac Surgery, Friedrich-Alexander University, Erlangen-Nürnberg, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Ramsperger-Gleixner
authors.affiliation: Department of Cardiac Surgery, Friedrich-Alexander University, Erlangen-Nürnberg, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Koch
authors.affiliation: Department of Medicine 5, Friedrich-Alexander University, Erlangen-Nürnberg, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Goldmann
authors.affiliation: Department of Medicine 5, Friedrich-Alexander University, Erlangen-Nürnberg, Germany.
authors.forename: Bernd M
authors.initials: BM
authors.lastname: Spriewald
authors.affiliation: Department of Cardiac Surgery, Friedrich-Alexander University, Erlangen-Nürnberg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Weyand
authors.affiliation: Department of Cardiac Surgery, Friedrich-Alexander University, Erlangen-Nürnberg, Germany sensminger@hdz-nrw.de.
authors.forename: Stephan M
authors.initials: SM
authors.lastname: Ensminger
mesh_terms: D064591:Allografts / Q000187:drug effects / Q000276:immunology*; D000818:Animals; D001011:Aorta / Q000737:chemistry / Q000473:pathology; D001161:Arteriosclerosis / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control; D000077144:Clopidogrel; D018450:Disease Progression; D000068338:Everolimus; D056724:Immunity, Humoral / Q000187:drug effects; D007518:Isoantibodies; D051379:Mice; D008810:Mice, Inbred C57BL; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D007518:Isoantibodies; D000068338:Everolimus; D000077144:Clopidogrel; D013988:Ticlopidine; D020123:Sirolimus
keywords: Clopidogrel; Humoral immunity; Platelets; Transplant arteriosclerosis; mTOR inhibitor