Induction of indefinite survival of fully mismatched cardiac allografts and generation of regulatory cells by sarpogrelate hydrochloride.
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.
Akiyoshi
Takurin
T
Department of Surgery, Keio University School of Medicine, Tokyo, Japan.
Zhang
Qi
Q
Inoue
Fumihiko
F
Aramaki
Osamu
O
Hatano
Minoru
M
Shimazu
Motohide
M
Kitajima
Masaki
M
Shirasugi
Nozomu
N
Niimi
Masanori
M
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*
D012702:Serotonin Antagonists; D013386:Succinates; D018799:Intercellular Adhesion Molecule-1; D016753:Interleukin-10; C064294:sarpogrelate; D015847:Interleukin-4