免疫系统
外周血单个核细胞
肾
刺激
寡核苷酸
脾脏
细胞因子
药理学
分子生物学
生物
化学
免疫学
生物化学
内分泌学
体外
DNA
作者
Scott P. Henry,K. Stecker,Donald E. Brooks,David Monteith,Boyd Conklin,C. Frank Bennett
出处
期刊:PubMed
日期:2000-02-01
卷期号:292 (2): 468-79
被引量:67
摘要
Phosphorothioate oligodeoxynucleotides produce splenomegaly and mononuclear cell infiltrates in multiple organs in mice after repeated i.v. administration. Several phosphorothioate oligodeoxynucleotides were studied to better understand the basis of immunostimulatory properties of these molecules in mice and to study the effects of chemically modified oligonucleotides. Chemical modifications examined included 5-methyl cytosine and 2'-methoxyethoxy substituents. Male mice (six per group) were treated with oligonucleotide concentrations of 0, 2, 10, or 50 mg/kg by i.v. injection every other day for 14 days. Immune stimulation was assessed 24 h after the last dose by measuring spleen weight, or histologic and immunohistochemical examination of liver and kidney. Immune stimulation was dose-dependent for the phosphorothioate oligodeoxynucleotides studied, but potency varied as a function of sequence. Results from this study reveal that there is a close correlation between the extent of splenomegaly and other evidence of immune stimulation, such as the severity of cell infiltrates in liver and kidney in mice. Immunohistochemical analysis indicated that cell infiltrates in liver and kidney were primarily mononuclear cells associated with increased expression of the endothelial-leukocyte cellular adhesion molecule intracellular adhesion molecule-1 and the cytokine interleukin-6. Immune stimulation was markedly decreased with oligonucleotides containing the 5-methyl cytosine and further decreased by 2'-methoxyethoxy modifications. Administration of these modified oligonucleotides to mice did not produce splenomegaly even at the 50-mg/kg dose, and only produced minimal cell infiltrates despite the presence of comparable or greater tissue oligonucleotide concentrations. Thus, chemical modifications appeared to increase the tolerability profile for these compounds that are representative of the second generation of antisense oligonucleotides.
科研通智能强力驱动
Strongly Powered by AbleSci AI