Thiele D L, Bryde S E, Lipsky P E
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas 75235.
J Immunol. 1988 Nov 15;141(10):3377-82.
Treatment of C57BL/6J (B6) murine splenocytes with L-leucyl-L-leucine methyl ester (Leu-Leu-OMe) selectively removes NK cells, CTL precursors, and the capacity to cause lethal graft-vs-host disease (GVHD) in irradiated B6 X DBA/2 F1 mice. In contrast, alloantigen-induced L3T4(+) Th cell function has been shown to be relatively preserved after exposure to this agent. The present studies assessed the effects of Leu-Leu-OMe treatment of donor cells on induction of lethal GVHD in other murine strain combinations. When irradiated B6 X CBAF1 mice were infused with T and NK cell-depleted B6 bone marrow cells and 3 to 30 X 10(6) B6 spleen cells, uniformly lethal GVHD was observed. However, B6 X CBAF1 recipients of T and NK-depleted B6 bone marrow cells and similar numbers of Leu-Leu-OMe-treated B6 spleen cells demonstrated 90 to 100% long term survival. In contrast, Leu-Leu-OMe treatment of B6 donor cells had no beneficial effect on mortality rates in irradiated (B6 X B6-C-H-2bm12)F1 (B6 X bm12F1) recipients. When B6 spleen cells were stimulated in vivo or in vitro with either B6 X CBAF1 or B6 X bm12F1 stimulator cells, the capacity to generate alloantigen-specific CTL was abolished comparably by Leu-Leu-OMe treatment. Thus, the dramatic difference between the effects of Leu-Leu-OMe treatment of B6 spleen cells on the course of GVHD in B6 x CBAF1 and class II MHC only disparate B6 x bm12F1 recipients could not be explained by unique resistance of bm12-specific CTL precursors to Leu-Leu-OMe. These findings indicate that T cell effector mechanisms distinct from classic cell-mediated cytotoxicity are sufficient to generate lethal GVHD in class II MHC only disparate B6----B6 X bm12F1 mice.
用L-亮氨酰-L-亮氨酸甲酯（Leu-Leu-OMe）处理C57BL/6J（B6）小鼠脾细胞，可选择性去除自然杀伤细胞（NK细胞）、细胞毒性T淋巴细胞（CTL）前体以及在受辐照的B6×DBA/2 F1小鼠中引发致死性移植物抗宿主病（GVHD）的能力。相比之下，已证明同种异体抗原诱导的L3T4(+)辅助性T细胞（Th细胞）功能在接触该试剂后相对保持不变。本研究评估了用Leu-Leu-OMe处理供体细胞对其他小鼠品系组合中致死性GVHD诱导的影响。当给受辐照的B6×CBAF1小鼠输注去除T细胞和NK细胞的B6骨髓细胞以及3至30×10(6)个B6脾细胞时，观察到一致的致死性GVHD。然而，接受去除T细胞和NK细胞的B6骨髓细胞以及相似数量经Leu-Leu-OMe处理的B6脾细胞的B6×CBAF1受体显示出90%至100%的长期存活率。相比之下，用Leu-Leu-OMe处理B6供体细胞对受辐照的（B6×B6-C-H-2bm12）F1（B6×bm12F1）受体的死亡率没有有益影响。当用B6×CBAF1或B6×bm12F1刺激细胞在体内或体外刺激B6脾细胞时，Leu-Leu-OMe处理同等程度地消除了产生同种异体抗原特异性CTL的能力。因此，Leu-Leu-OMe处理B6脾细胞对B6×CBAF1和仅在II类主要组织相容性复合体（MHC）上存在差异的B6×bm12F1受体中GVHD进程的影响之间的显著差异，无法用bm12特异性CTL前体对Leu-Leu-OMe的独特抗性来解释。这些发现表明，不同于经典细胞介导细胞毒性的T细胞效应机制足以在仅在II类MHC上存在差异的B6----B6×bm12F1小鼠中产生致死性GVHD。
