Prolongation of survival of fully allogeneic cardiac grafts and generation of regulatory cells by a histamine receptor 2 antagonist.
BACKGROUND
The effects of histamine on immunologic responses via the histamine receptor 2 (HR2) have been studied, but few investigations explored the immunomodulatory role of histamine in vivo. We examined whether the HR2 antagonist ranitidine affects the alloimmune response in a murine model of cardiac transplantation.


METHODS
CBA (H-2k) recipients were given no treatment or one intravenous injection of ranitidine on the day of transplantation of a heart from C57BL/10 (H-2b) donors. Survival of the allografts was recorded. The effect of the ranitidine treatment on cell proliferation and cytokine production was assessed by mixed leukocyte culture and enzyme-linked immunosorbent assays. An adoptive transfer study was conducted to determine whether regulatory cells were generated. The effect on graft survival of adding FK506 to the ranitidine treatment was also examined.


RESULTS
CBA recipients given ranitidine (60 mg/kg) had prolonged graft survival (median survival time [MST], 87 days). Ranitidine treatment also suppressed the proliferation of splenocytes and production of interleukin (IL)-2 and up-regulated IL-10 production. Adoptive transfer of splenocytes and CD4 cells from ranitidine-treated allograft recipients induced significant prolongation of allograft survival in naive secondary recipients (MST, 71 and >100 days, respectively). CBA recipients given both ranitidine and FK506 (0.1 mg/kg/day for 14 days) had indefinite survival of cardiac allografts (MST, >100 days). CBA recipients treated with FK506 alone rejected the allografts (MST, 27 days).


CONCLUSIONS
In our model, ranitidine treatment induced significantly prolonged survival of fully allogeneic cardiac grafts, generated CD4 regulatory cells, and indefinite survival when combined with FK506 (0.1 mg/kg/day).
Department of Surgery, Keio University School of Medicine, 35 Shinanomachi, Tokyo, Japan.
Fumihiko
F
Inoue
Qi
Q
Zhang
Takurin
T
Akiyoshi
Osamu
O
Aramaki
Daiki
D
Iwami
Kenji
K
Matsumoto
Yuko
Y
Kitagawa
Nozomu
N
Shirasugi
Masanori
M
Niimi
D019264:Adoptive Transfer; D000818:Animals; D016207:Cytokines / Q000097:blood; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D016027:Heart Transplantation / Q000276:immunology / Q000502:physiology*; D006634:Histamine H1 Antagonists / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D011899:Ranitidine / Q000627:therapeutic use*; D011968:Receptors, Histamine; D014184:Transplantation, Homologous / Q000502:physiology; D014185:Transplantation, Isogeneic / Q000502:physiology
D016207:Cytokines; D006634:Histamine H1 Antagonists; D011968:Receptors, Histamine; D011899:Ranitidine