IMMUNE STIMULATION - A CLASS EFFECT OF PHOSPHOROTHIOATE OLIGODEOXYNUCLEOTIDES IN RODENTS

Treatment of rodents with phosphorothioate oligodeoxynucleotides induc es a form of immune stimulation characterized by splenomegaly, lymphoi d hyperplasia, hypergammaglobulinemia and mixed mononuclear cellular i nfiltrates in numerous tissues. Immune stimulation was evaluated in mi ce with in vivo and in vitro studies using a review of historical data and specific in vivo and in vitro studies. All phosphorothioate oligo deoxynucleotides evaluated induced splenomegaly and B-lymphocyte proli feration. Splenomegaly and B-lymphocyte proliferation increased with d ose or concentration of oligodeoxynucleotide. Splenomegaly appeared to occur, at least in part, as a result of stimulation of B-lymphocyte p roliferation. There were differences with respect to degree or potency of immune stimulation by different oligodeoxynucleotides. The rank or der potencies for B-lymphocyte proliferation in vitro and splenomegaly correlated well for the oligodeoxynucleotides tested. Particular olig odeoxynucleotide sequence motifs or palindromes have been demonstrated to affect in vitro cell proliferation. Inclusion of a 5'-AACGTT-3' pa lindrome in a phosphorothioate oligodeoxynucleotide sequence significa ntly enhanced the potency. While inclusion of this palindrome or a CpG motif alone may contribute to the immune stimulation, these palindrom es and motifs were clearly not the sole factor required for immune sti mulation. Several phosphorothioate oligodeoxynucleotides that did not contain a CpG motif still induced immune stimulation in mice. The immu ne stimulation induced by phosphorothioate oligodeoxynucleotides was a n effect of this class of compounds to which rodents are acutely sensi tive.