| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2012: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2011: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
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| Research Abstract |
It has been reported that portal hypertension leads to liver sinusoid cells including liver sinusoidal endotherial cells (LSECs), which are supposed to have tolerogenic capacity. We found that the incidence of acute rejection episode was significantly higher in portal hypertension patients after living-donor liver transplantation (LDLT). This fact prompted us to investigate the influence of postoperative portal vein pressure (PVP) on alloimmune response in recipient after LDLT. To investigate mechanism, we performed allogeneic co-culture assay using 70% hepatectomized (HTx) mouse model with or without porto-systemic shunt. In this assay, 3 days after HTx, digested whole hepatic constituent cells (HCs) of Balb/c mice were co-cultured with allogeneic B6 splenocytes, and B6 T-cell proliferation was quantified. Further, we performed phenotypic analysis of the LSECs and dendritic cells in the livers of these mice. The co-culture assay revealed that Balb/c HCs from HTx mice without shunt ind
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uced a significantly higher anti-Balb/c response of B6 T cells than those from untreated mice. However, this accelerated B6 T-cell response was significantly reduced in HTx mice with shunt. Phenotypic analysis revealed that LSECs from HTx mice without shunt significantly down-regulated their expressions of MHC class II, while those from Htx mice with shunt recovered their expression of MHC class II. The phenotype of dendritic cells showed no significant change. These results suggest that postoperative portal hypertension promotes alloimmune responses in recipients after LDLT, at least in part, by impairing antigen presenting capacity of LSECs. We then applied a continuous portal infusion of prostaglandin E1 (PGE1) for portal decompression to the treatment of LDLT recipients with small-for-size grafts and investigated the impact of this treatment on post-operative alloimmune responses in patients. The temporal portal infusion of PGE1 significantly attenuated portal hypertension as well as anti-donor T cell responses and clinical rejection In conclusion, our findings present a novel concept to prevent an acceleration of alloimmune responses by controlling portal vein pressure after LDLT. Less
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