RNA degradation precedes DNA cleavage in autoreactive CD4 T cells suppressed by calicheamicin gamma1.
RNA degradation precedes DNA cleavage in autoreactive CD4 T cells suppressed by calicheamicin gamma1.
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DOI：
10.1016/j.intimp.2004.01.002
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发表时间：
2004-04
影响因子：
5.6
通讯作者：
Sunil Thomas;Anca Preda-Pais;S. Casares;T. Brumeanu
中科院分区：
文献类型：
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作者：
Sunil Thomas;Anca Preda-Pais;S. Casares;T. Brumeanu
Calicheamicinγ1(CalCalγ1)是一种疏水烯二炔类抗生素，能切割脱氧核糖核酸并导致多种细胞的凋亡。在这里，我们表明，CALγ1对抗原特异性(糖尿病)和NAı̈ve CD4T细胞的抑制作用是另一种强凋亡药物多柔比星(Dox)的1000倍。Calγ1与胸腺前体细胞和成熟T细胞孵育30min后，免疫原肽或CD3和CD2 8抗体刺激胸腺前体细胞和成熟T细胞后，细胞因子的产生和增殖能力急剧下降或丧失。CalDNA 1的抑制作用与γ的快速、非选择性降解有关，而DNA的裂解发生在较晚的时间点和较高的剂量。CALγ1可能是一种潜在的治疗剂，可以消除自身免疫性疾病中的自我反应性T细胞，前提是它是由抗原特异性T细胞配体传递的。将CAL-γ-1等高抑制性药物靶向自身反应性T细胞，可显著减少治疗剂量和药物相关副作用。
Calicheamicin γ1 (Cal γ1) is a hydrophobic enediyne antibiotic known to cleave the DNA and lead to apoptosis in a variety of cells. Herein, we show that Cal γ1 exhibits a 1000-times stronger suppressogenic effect on antigen-specific (diabetogenic), and naı̈ve CD4 T cells than Doxorubicin (Dox), another strong apoptotic drug. The thymic precursors and mature T cells incubated with Cal γ1 for only 30 min showed a drastic decrease or loss of cytokine production and proliferation following stimulation with the immunogenic peptide, or with CD3 and CD28 antibodies. The suppressogenicity of Cal γ1 correlated with a rapid and non-selective degradation of RNA, whereas the DNA cleavage occurred at a later time point and at higher doses. Cal γ1 may represent a potential therapeutic agent to eliminate self-reactive T cells in autoimmune diseases, providing that is delivered by antigen-specific T-cell ligands. Targeting of highly suppressogenic drugs such as Cal γ1 to autoreactive T cells may reduce considerable the therapeutic dose and the drug-related side effects.