Satoru Akashi

A novel small-molecule compound targeting CCR5 and CXCR3 prevents acute and chronic allograft rejection.

Background. Chemokines and chemokine receptors are critical in leukocyte recruitment, activation, and differentiation. Among them, CC chemokine receptor 5 (CCR5) and CXC chemokine receptor 3 (CXCR3) have been reported to play important roles in alloimmune responses and may be potential targets for posttransplant immunosuppression. Methods. Fully major histocompatibility complex (MHC)-mismatched murine cardiac and islet transplant models were used to test the effect in vivo of a novel, small-molecule compound TAK-779 by targeting CCR5 and CXCR3 in acute allograft rejection. An MHC class II mismatched cardiac transplant model was used to evaluate its efficacy in chronic allograft rejection. Intragraft expression of cytokines, chemokines, and chemokine receptors was measured by quantitative real-time polymerase chain reaction and by histological analysis. Results. Treatment of TAK-779 significantly prolonged allograft survival across the MHC barrier in two distinct transplant models. The treatment downregulated local immune activation as observed by the reduced expression of several chemokines, cytokines, and chemokine receptors. Thereby, the recruitment of CD4, CD8, and CD11c cells into transplanted allografts were inhibited. Furthermore, TAK-779 treatment significantly attenuated the development of chronic vasculopathy, fibrosis, and cellular infiltration. Conclusions. Antagonism of CCR5 and CXCR3 has a substantial therapeutic effect on inhibiting both acute and chronic allograft rejection. CCR5 and CXCR3 are functional in the process of allograft rejection and may be potential targets in clinical transplantation in the future.

Significance and therapeutic potential of prostaglandin E2 receptor in hepatic ischemia/reperfusion injury in mice

Prostaglandin E2 (PGE2) mediates a variety of innate and adaptive immunity through four distinct receptors: EP1‐EP4. It has been suggested that each EP plays a unique and pivotal role in various disease conditions. We investigated the pathophysiological role of EP receptors in hepatic ischemia/reperfusion (I/R) injury. In this study, a 70% hepatic ischemic model was used in male C57BL/6 mice. Selective EP agonists were used to clarify the function of each PGE2 receptor in I/R injury. Although all four receptors were expressed in the naïve liver, EP4 expression was significantly upregulated after hepatic I/R. Although EP1, 2, or 3 agonists did not show any protective effect on liver function, the EP4 agonist significantly inhibited hepatic I/R injury as determined by serological and histological analyses. Furthermore, the EP4 agonist downregulated the local expressions of several proinflammatory cytokines, chemokines, and adhesion molecules in the early phase of reperfusion. In contrast, it augmented the local expression of an anti‐inflammatory cytokine, interleukin 10. Additionally, the neutrophil accumulation was also inhibited by EP4 agonist treatment. Finally, to confirm the therapeutic efficacy of the EP4 agonist in hepatic I/R injury, the nonischemic shunt liver was removed after 120 minutes of ischemia, resulting in the death of 86% of control mice within 48 hours. In sharp contrast, 80% of mice treated with the EP4 agonist survived. In conclusion, the PGE2‐EP4 signaling pathway has an inhibitory role in hepatic I/R injury. An EP4 agonist effectively protects against ischemic injury. (HEPATOLOGY 2005.)

A Case of Splenic Metastasis from Hepatocellular Carcinoma

症例は55歳の男性で, 平成8年2月前区域を中心とする巨大肝細胞癌に対して拡大右葉切除術施行した. その後, 残肝再発, 両側肺転移を来し, TAEを2度, 肺切除を2度施行した. 平成13年11月脾臓に径2.5cmの腫瘍を認めたため, 精査目的に平成14年1月入院. 腹部超音波検査にて腫瘍は径5cmにまで増大していた. 血管造影上, 腫瘍濃染は認めなかったが, 肝細胞癌脾転移と診断し, 手術を施行した. 腫瘍は大部分が脾被膜に覆われて存在していたが, 一部は横隔膜に浸潤しており, 横隔膜・肝臓の一部も合併切除した. 切除標本においても, 腫瘍はほぼ全体が脾実質内に存在していた. 術後3年経過した現在, 無再発生存中である. 肝細胞癌の単発性脾転移はまれであり予後不良例が多いが, 本症例のように他病変がコントロール可能であれば, 切除により良好な予後が期待できる.