Thiele D L, Lipsky P E
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas 75235.
Proc Natl Acad Sci U S A. 1990 Jan;87(1):83-7. doi: 10.1073/pnas.87.1.83.
Exposure of murine or human lymphocytes to L-leucyl-L-leucine methyl ester (Leu-Leu-OMe) results in selective killing of cytotoxic lymphocytes, whereas helper T cells and B cells remain functionally intact. Cytolytic lymphocytes incubated in the presence of toxic concentrations of Leu-Leu-OMe were found to contain membranolytic metabolites of the structure (Leu-Leu)n-OMe, where n greater than or equal to 3. The sensitivity of cytotoxic lymphocytes to Leu-Leu-OMe was found to be dependent upon production of these metabolites by a lysosomal thiol protease, dipeptidyl peptidase I, which is present at far higher levels in cytotoxic lymphocytes than in cells without cytolytic potential or not of bone marrow origin. Thus, this granule enzyme is required for the unique effects of Leu-Leu-OMe and may provide a target for the development of other immunotherapeutic agents designed to delete cytotoxic lymphocyte responses.
将小鼠或人类淋巴细胞暴露于L-亮氨酰-L-亮氨酸甲酯（Leu-Leu-OMe）会导致细胞毒性淋巴细胞被选择性杀伤，而辅助性T细胞和B细胞的功能仍保持完整。在有毒浓度的Leu-Leu-OMe存在下孵育的溶细胞性淋巴细胞被发现含有结构为(Leu-Leu)n-OMe的膜溶解代谢产物，其中n大于或等于3。细胞毒性淋巴细胞对Leu-Leu-OMe的敏感性被发现取决于溶酶体硫醇蛋白酶二肽基肽酶I产生的这些代谢产物，该酶在细胞毒性淋巴细胞中的含量远高于无溶细胞潜能的细胞或非骨髓来源的细胞。因此，这种颗粒酶是Leu-Leu-OMe独特作用所必需的，并且可能为开发其他旨在消除细胞毒性淋巴细胞反应的免疫治疗药物提供一个靶点。
