title: Induction of indefinite survival of fully mismatched cardiac allografts and generation of regulatory cells by sarpogrelate hydrochloride.
abstract: BACKGROUND
  At initiation of the immunologic response, platelets rapidly release chemical mediators such as serotonin (5-hydroxytryptamine, [5-HT]) and cytokines. Sarpogrelate hydrochloride (SH), a selective 5-HT2-receptor antagonist, is used to treat patients with peripheral arterial disease. We investigated the effect of SH on the alloimmune response in a murine cardiac transplantation model.
  
  
  METHODS
  CBA mice underwent transplantation of a C57BL/10 heart and received a short course of SH treatment. Survival of the allograft was recorded. An adoptive transfer study was performed to determine whether regulatory cells were generated. Immunohistochemistry studies of intercellular adhesion molecule 1 (ICAM-1), histological, cell-proliferation, and cytokine assessments were performed.
  
  
  RESULTS
  Untreated CBA mice rejected C57BL/10 cardiac grafts acutely (median survival time [MST], 8 days). In mice given 10 mg/kg of SH, all allografts survived indefinitely (MST, >100 days); these mice also had significantly prolonged survival of donor-specific skin grafts but acute rejection of third-party skin grafts. Secondary CBA recipients given not only whole but also CD4 splenocytes from primary SH-treated CBA recipients with C57BL/10 cardiac allograft had indefinite survival of C57BL/10 hearts (MST, >100 days). SH inhibited upregulation of ICAM-1 on endothelial cells in the allografts. Graft acceptance and hyporesponsiveness were confirmed by the histological and cell-proliferation studies, respectively. Production of interleukin-4 and interleukin-10 from splenocytes of SH-treated transplant recipients increased compared to that from splenocytes of untreated recipients.
  
  
  CONCLUSIONS
  SH induced indefinite survival of fully allogeneic cardiac allografts, generated CD4 regulatory cells, inhibited ICAM-1 expression in the allografts, and upregulated IL-4 and IL-10 production.
authors.affiliation: Department of Surgery, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Takurin
authors.initials: T
authors.lastname: Akiyoshi
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Inoue
authors.forename: Osamu
authors.initials: O
authors.lastname: Aramaki
authors.forename: Minoru
authors.initials: M
authors.lastname: Hatano
authors.forename: Motohide
authors.initials: M
authors.lastname: Shimazu
authors.forename: Masaki
authors.initials: M
authors.lastname: Kitajima
authors.forename: Nozomu
authors.initials: N
authors.lastname: Shirasugi
authors.forename: Masanori
authors.initials: M
authors.lastname: Niimi
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D016027:Heart Transplantation / Q000379:methods*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D012702:Serotonin Antagonists / Q000494:pharmacology; D013154:Spleen / Q000166:cytology; D013386:Succinates / Q000494:pharmacology*
chemical_list: D012702:Serotonin Antagonists; D013386:Succinates; D018799:Intercellular Adhesion Molecule-1; D016753:Interleukin-10; C064294:sarpogrelate; D015847:Interleukin-4