Bowlin T L, Davis G F, McKown B J
Merrell Dow Research Institute, Cincinnati, Ohio 45215.
Cell Immunol. 1988 Feb;111(2):443-50. doi: 10.1016/0008-8749(88)90107-4.
The objective of the present investigation was to examine the effect of a new potent irreversible inhibitor of ornithine decarboxylase, (2R,5R)-6-heptyne-2,5-diamine (MAP) (MDL 72,175), on the induction of functionally reactive T-cell populations in vitro. We examined alloantigen-activated cytolytic T lymphocytes (CTL) and T-helper (TH) lymphocytes generated during a one-way mixed-leukocyte culture (MLC). The addition of MAP (1 mM) at the initiation of cell culture reduced intracellular putrescine, spermidine, and spermine levels by 81.9, 82.4, and 55.8% respectively. MAP reduced CTL induction 93.8, 78.4, and 37.5% when added at 0, 24, or 48 hr of culture, respectively. A dose-dependent inhibition of CTL induction and polyamine levels was observed following MAP treatment. In direct comparison with another ODC inhibitor, alpha-difluoromethylornithine (DFMO), MAP was five- to sixfold more potent in reducing CTL induction. CTL generation is dependent upon the endogenous production of the TH-cell product interleukin 2 (IL-2). MAP treatment reduced detectable IL-2 activity in a MLC by 54.8%. These results indicate that MAP is a potent inhibitor of alloantigen-activated CTL in vitro and deserves further investigation as a potential immunosuppressive agent.
本研究的目的是检测一种新型强效鸟氨酸脱羧酶不可逆抑制剂（2R,5R）-6-庚炔-2,5-二胺（MAP）（MDL 72,175）对体外诱导功能性反应性T细胞群体的影响。我们检测了单向混合淋巴细胞培养（MLC）过程中产生的同种异体抗原激活的细胞毒性T淋巴细胞（CTL）和T辅助（TH）淋巴细胞。在细胞培养开始时添加MAP（1 mM）可使细胞内腐胺、亚精胺和精胺水平分别降低81.9%、82.4%和55.8%。分别在培养0、24或48小时时添加MAP，其对CTL诱导的抑制率分别为93.8%、78.4%和37.5%。MAP处理后观察到CTL诱导和多胺水平呈剂量依赖性抑制。与另一种鸟氨酸脱羧酶抑制剂α-二氟甲基鸟氨酸（DFMO）直接比较，MAP在降低CTL诱导方面的效力高五到六倍。CTL的产生依赖于TH细胞产物白细胞介素2（IL-2）的内源性产生。MAP处理使MLC中可检测到的IL-2活性降低了54.8%。这些结果表明，MAP是体外同种异体抗原激活的CTL的强效抑制剂，作为一种潜在的免疫抑制剂值得进一步研究。
