Background: Several studies have shown that angiotensin II type 1 receptor (AT1 receptor) blockade reduced graft arteriosclerosis and immune-mediated graft damages. Here, we investigated the ability of olmesartan, AT1 receptor blocker, to inhibit alloimmune responses in fully mismatched mouse transplantation model. Methods & Results: First, to determine the ability of olmesartan for inhibiting alloimmune responses in vitro, MLR experiments were performed. Various amounts of olmesartan were added to the MLC with naÏve CBA responder and MMC-treated C57BL/10 stimulator cells. Addition of olmesartan to an allo-MLC inhibited proliferation of naÏve CBA responders against MMC-treated C57BL/10 stimulators in a dose-dependent manner. Next, to determine the ability of olmesartan for inhibiting alloimmune responses in vivo, cardiac transplantation experiments were performed. Hearts from C57BL/10 (B10: H-2b) mice were transplanted into CBA (H-2k) recipients treated with olmesartan intravenously on day 0 (the day of transplantation) and thereafter intraperitoneally on day 2, 4, 6, 8, and 10. Untreated CBA recipients and recipients given 0.1mg/kg/day of olmesartan rejected B10 hearts acutely (median survival time [MST], 7.5 and 9 days, respectively, n=6 and 5). With a dose of 1mg/kg/day of olmesartan, survival of fully mismatched cardiac allografts was significantly prolonged (MST, 38.5 days, n=12, p < 0.05 compared to that in untreated recipients). To determine whether regulatory cells were generated, adoptive transfer studies were conducted. Fourteen days after CBA mice (primary recipients) underwent transplantation of a B10 heart and treatment with 1.0 g/kg/day of olmesartan, whole (5 x 10⁷) splenocytes from primary recipients with functioning allografts were adoptively transferred into naive CBA mice (secondary recipients). Immediately afterward, the secondary recipients underwent transplantation of a B10 heart. The secondary recipients with the adoptive transfer of splenocytes from the primary recipients with olmesartan treatment had significantly prolonged survival of cardiac allografts (MST, 43 days, n=8). In contrast, the control secondary recipients with adoptive transfer of naive splenocytes eventually rejected allografts (MST, 14 days, n=6). Conclusion: In our model, treatment with olmesartan induced significantly prolonged survival of fully allogeneic cardiac grafts and generated regulatory cells.

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