Yokoyama Takeshi, Aramaki Osamu, Takayama Tadatoshi, Takano Seigo, Zhang Qi, Shimazu Motohide, Kitajima Masaki, Ikeda Yoshifumi, Shirasugi Nozomu, Niimi Masanori
Department of Surgery of Nihon University School of Medicine, Tokyo, Japan.
J Thorac Cardiovasc Surg. 2005 Oct;130(4):1167-74. doi: 10.1016/j.jtcvs.2005.06.031.
Selective inhibition of cyclooxygenase 2 has been reported to have not only anti-inflammatory effects but also effects on the immune response. We investigated ability of a cyclooxygenase 2 inhibitor to inhibit alloimmune response in a murine cardiac transplantation model.
CBA (H2(k)) mice underwent transplantation of C57BL/10 (H2(b)) hearts. On the day of transplantation, the recipients received either no treatment or single administration of aspirin (a cyclooxygenase 1 and 2 inhibitor) or the selective cyclooxygenase 2 inhibitor NS-398. Naive CBA mice (secondary recipients) underwent adoptive transfer of splenocytes from treated mice with long-surviving grafts (primary recipients) to determine whether regulatory cells developed after NS-398 treatment. Histologic, cell-proliferation, and cytokine studies were also performed.
Untreated CBA mice rejected C57BL/10 cardiac grafts acutely (median survival time, 8 days). The majority of recipients given aspirin rejected their grafts within 20 days (median survival time, 11 days). In mice given NS-398, the majority of the grafts survived indefinitely (median survival time, >100 days). Secondary CBA recipients given CD4+ splenocytes from primary CBA recipients treated with NS-398 also had indefinite survival of C57BL/10 hearts (median survival time, >60 days). Graft acceptance and proliferative hyporesponsiveness were also confirmed by the histologic and cell-proliferation studies, respectively. Production of interleukin 4 and 10 from splenocytes of the recipients treated with NS-398 were significantly higher than that from untreated recipients.
In our model administration of cyclooxygenase 2 inhibitor induced indefinite survival of fully mismatched cardiac grafts and generated CD4+ regulatory cells. Cyclooxygenase 2 inhibitor could warrant consideration for use as an immunomodulating agent in clinical transplantation.
据报道，环氧合酶2的选择性抑制不仅具有抗炎作用，还对免疫反应有影响。我们在小鼠心脏移植模型中研究了一种环氧合酶2抑制剂抑制同种免疫反应的能力。
CBA（H2(k)）小鼠接受C57BL/10（H2(b)）心脏移植。在移植当天，受体小鼠要么不接受治疗，要么单次给予阿司匹林（一种环氧合酶1和2抑制剂）或选择性环氧合酶2抑制剂NS-398。未处理的CBA小鼠（二级受体）接受来自长期存活移植物的处理小鼠（一级受体）的脾细胞过继转移，以确定NS-398处理后是否产生了调节性细胞。还进行了组织学、细胞增殖和细胞因子研究。
未处理的CBA小鼠急性排斥C57BL/10心脏移植物（中位存活时间，8天）。大多数给予阿司匹林的受体在20天内排斥其移植物（中位存活时间，11天）。给予NS-398的小鼠中，大多数移植物无限期存活（中位存活时间，>100天）。接受来自用NS-398处理的一级CBA受体的CD4+脾细胞的二级CBA受体，C57BL/10心脏也无限期存活（中位存活时间，>60天）。组织学和细胞增殖研究分别证实了移植物的接受和增殖低反应性。用NS-398处理的受体脾细胞产生的白细胞介素4和10明显高于未处理的受体。
在我们的模型中，给予环氧合酶2抑制剂可诱导完全不匹配心脏移植物无限期存活并产生CD4+调节性细胞。环氧合酶2抑制剂在临床移植中作为免疫调节剂使用值得考虑。
