The immunosuppressive activity of L-leucyl-L-leucine methyl ester: selective ablation of cytotoxic lymphocytes and monocytes.
The immunosuppressive activity of L-leucyl-L-leucine methyl ester: selective ablation of cytotoxic lymphocytes and monocytes.
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DOI：
10.4049/jimmunol.136.3.1038
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发表时间：
1986-02
影响因子：
4.4
通讯作者：
D. Thiele;P. Lipsky
中科院分区：
文献类型：
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作者：
D. Thiele;P. Lipsky
L-亮氨酰-L-亮氨酸甲酯(Leu-Leuome)是人单核细胞或多形核白细胞产生的L-亮氨酸甲酯的二肽缩合产物，可完全消除混合淋巴细胞的自然杀伤细胞(NK)功能。在本研究中，我们考察了Leu-Leu-ome作用的特异性。研究发现，各种非淋巴来源的组织培养细胞和肿瘤株对任何明显的Leu-Leu-ome介导的毒性都是完全耐药的。此外，红白血病细胞株K562、T细胞株Molt-4、B细胞株HS-Sultan和Daudi以及EBV转化的B细胞株不受该化合物完全消除NK细胞的浓度的影响。同样，绝大多数OKT4+淋巴细胞在暴露于Leu-Leu-ome后没有表现出明显的毒性。此外，它们保留了对同种异体细胞正常增殖的能力，以及为免疫球蛋白分泌细胞(ISC)的生成提供帮助的能力。然而，Leu-Leu-ome导致混合淋巴细胞群体中OKT8+细胞的部分耗竭。暴露后，剩余的OKT8+细胞仍能在混合淋巴细胞培养中增殖，但它们对ISC生成的抑制作用被取消。此外，混合淋巴细胞培养中产生的细胞毒性T淋巴细胞(CTL)的前体和激活的效应物以及激活的NK样活性都被低浓度的Leu-Leu-ome所消除。确实，OKT4+和OKT8+CTL都被Leu-Leu-ome消除。此外，外周血M Phi细胞和具有许多M Phi相似特征的人类细胞系U937细胞对Leu-Leu-Me介导的毒性都很敏感，尽管浓度只比完全消除NK细胞的浓度高2到5倍。这些结果表明，Leu-Leu-ome对NK细胞、CTL和M Phi具有选择性毒性，而对其他多种淋巴或非淋巴细胞类型无不良反应。
L-Leucyl-L-leucine methyl ester (Leu-Leu-OMe), a dipeptide condensation product of L-leucine methyl ester generated by human monocytes (M phi) or polymorphonuclear leukocytes, eliminates all natural killer cell (NK) function from mixed lymphocyte populations. In the present studies, the specificity of the action of Leu-Leu-OMe was examined. It was found that a variety of tissue culture cells and tumor lines of nonlymphoid origin were completely resistant to any demonstrable Leu-Leu-OMe-mediated toxicity. Furthermore, the erythroleukemia line K562, the T cell line Molt-4, the B cell lines HS-Sultan and Daudi, and EBV-transformed B cell lines were unaffected by concentrations of this compound that completely eliminated NK cells. Similarly, the vast majority of OKT4+ lymphocytes manifested no significant toxicity after Leu-Leu-OMe exposure. Furthermore, they retained the capacity to proliferate normally in response to allogeneic cells as well as the ability to provide help for the generation of immunoglobulin-secreting cells (ISC). However, Leu-Leu-OMe caused partial depletion of OKT8+ cells from mixed populations of lymphocytes. After such exposure, the remaining OKT8+ cells were still capable of proliferating in mixed lymphocyte cultures, but the suppressive effect of these cells on ISC generation was abolished. Furthermore, both precursors and activated effectors of cytotoxic T lymphocyte (CTL) and activated NK-like activity generated in mixed lymphocyte cultures were eliminated by exposure to low concentrations of Leu-Leu-OMe. Indeed, both OKT4+ and OKT8+ CTL were eliminated by Leu-Leu-OMe. In addition, both peripheral blood M phi and U937 cells, a human cell line with many M phi-like characteristics, were sensitive to Leu-Leu-OMe-mediated toxicity, although only at two- to fivefold higher concentrations than those completely eliminating NK cells. These findings indicate that Leu-Leu-OMe has selective toxicity for NK cells, CTL, and M phi without adverse effects on a variety of other lymphoid or nonlymphoid cell types.