Immune stimulation--a class effect of phosphorothioate oligodeoxynucleotides in rodents.
Treatment of rodents with phosphorothioate oligodeoxynucleotides induces a form of immune stimulation characterized by splenomegaly, lymphoid hyperplasia, hypergammaglobulinemia and mixed mononuclear cellular infiltrates in numerous tissues. Immune stimulation was evaluated in mice with in vivo and in vitro studies using a review of historical data and specific in vivo and in vitro studies. All phosphorothioate oligodeoxynucleotides evaluated induced splenomegaly and B-lymphocyte proliferation. Splenomegaly and B-lymphocyte proliferation increased with dose or concentration of oligodeoxynucleotide. Splenomegaly appeared to occur, at least in part, as a result of stimulation of B-lymphocyte proliferation. There were differences with respect to degree or potency of immune stimulation by different oligodeoxynucleotides. The rank order potencies for B-lymphocyte proliferation in vitro and splenomegaly correlated well for the oligodeoxynucleotides tested. Particular oligodeoxynucleotide sequence motifs or palindromes have been demonstrated to affect in vitro cell proliferation. Inclusion of a 5'-AACGTT-3' palindrome in a phosphorothioate oligodeoxynucleotide sequence significantly enhanced the potency. While inclusion of this palindrome or a CpG motif alone may contribute to the immune stimulation, these palindromes and motifs were clearly not the sole factor required for immune stimulation. Several phosphorothioate oligodeoxynucleotides that did not contain a CpG motif still induced immune stimulation in mice. The immune stimulation induced by phosphorothioate oligodeoxynucleotides was an effect of this class of compounds to which rodents are acutely sensitive.
Monteith
D K
DK
Isis Pharmaceuticals, Carlsbad, CA 92008, USA.
Henry
S P
SP
Howard
R B
RB
Flournoy
S
S
Levin
A A
AA
Bennett
C F
CF
Crooke
S T
ST
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D001483:Base Sequence; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009841:Oligonucleotides / Q000494:pharmacology*; D013163:Splenomegaly / Q000139:chemically induced; D013268:Stimulation, Chemical; D013329:Structure-Activity Relationship; D013873:Thionucleotides / Q000494:pharmacology*
D000276:Adjuvants, Immunologic; D009841:Oligonucleotides; D013873:Thionucleotides