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Vol. 292, Issue 2, 468-479, February 2000
Isis Pharmaceuticals, Inc., Carlsbad, California.
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.
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