Itoi Hisayuki, Fujimori Yoshihiro, Tsutsui Hiroko, Matsui Kiyoshi, Sugihara Ayako, Terada Nobuyuki, Hada Toshikazu, Kakishita Eizo, Okamura Haruki, Hara Hiroshi, Nakanishi Kenji
Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan.
Transplantation. 2004 Nov 15;78(9):1245-50. doi: 10.1097/01.tp.0000137934.25190.b9.
Interleukin (IL)-18 stimulates T helper 1 (Th1)-mediated immune responses and the development of cytotoxic T lymphocytes (CTLs). Antihost CTLs are major effectors in acute graft-versus-host disease (aGvHD), a potentially fatal complication after allogeneic stem-cell transplantation. We investigated the relevant role of IL-18 in the development of aGvHD in mice.
Irradiated (C57BL/6x DBA/2) F1 (BDF1) mice transplanted with wild-type (WT) C57BL/6 (B6) splenocytes were compared with those transplanted with IL-18Ralpha-deficient B6 splenocytes with respect to Th1 development, CTL activity, severity of aGvHD, and survival.
Transplantation of WT B6 spleen cells into BDF1 mice induced aGvHD that was accompanied by elevation of both serum IL-18 levels and IL-18 receptor alpha chain (IL-18Ralpha) expression on engrafted T cells. The transplantation of WT B6 cells also induced high antihost CTL activity in host spleen, whereas transplantation of IL-18Ralpha-deficient B6 cells exhibited significantly reduced antihost-specific CTL activity, indicating that IL-18Ralpha-deficient CTLs were less cytotoxic than IL-18Ralpha-expressing CTLs. Moreover, the hosts receiving transplants with the IL-18Ralpha-deficient B6 cells had fewer fatal tissue injuries and increased their survival rates as compared with those receiving transplants with WT cells. Nevertheless, Th1 development in the hosts was the same, regardless of the type of donor cells.
These results suggest that Th1 induction and baseline CTL activity in aGvHD occur in the absence of IL-18, but endogenous IL-18 further accelerates aGvHD reaction to its full-blown manifestation. Thus, IL-18 may be involved in the development aGvHD by enhancing CTL activity.
白细胞介素（IL）-18刺激辅助性T细胞1（Th1）介导的免疫反应以及细胞毒性T淋巴细胞（CTL）的发育。抗宿主CTL是急性移植物抗宿主病（aGvHD）的主要效应细胞，aGvHD是异基因干细胞移植后一种潜在的致命并发症。我们研究了IL-18在小鼠aGvHD发生发展中的相关作用。
将接受野生型（WT）C57BL/6（B6）脾细胞移植的经辐照的（C57BL/6×DBA/2）F1（BDF1）小鼠与接受IL-18Rα缺陷型B6脾细胞移植的小鼠在Th1发育、CTL活性、aGvHD严重程度和存活率方面进行比较。
将WT B6脾细胞移植到BDF1小鼠中可诱发aGvHD，同时伴有血清IL-18水平升高以及移植的T细胞上IL-18受体α链（IL-18Rα）表达增加。WT B6细胞的移植还在宿主脾脏中诱导了高抗宿主CTL活性，而IL-18Rα缺陷型B6细胞的移植显示抗宿主特异性CTL活性显著降低，这表明IL-18Rα缺陷型CTL的细胞毒性低于表达IL-18Rα的CTL。此外，与接受WT细胞移植的宿主相比，接受IL-18Rα缺陷型B6细胞移植的宿主致命组织损伤更少，存活率更高。然而，无论供体细胞类型如何，宿主中的Th1发育情况相同。
这些结果表明，在没有IL-18的情况下，aGvHD中的Th1诱导和基线CTL活性依然会发生，但内源性IL-18会进一步加速aGvHD反应，使其发展为全面发作。因此，IL-18可能通过增强CTL活性参与aGvHD的发生发展。
