Suppressive oligodeoxynucleotides as a TLR antagonist : efforts to treat autoimmune diseases

Abstract

Synthetic oligodeoxynucleotides (ODN) expressing suppressive TTAGGG motifs effectively down-regulate the production of proinflammatory and Th1 cytokines elicited by a variety of Toll-Like Receptor (TLR) dependent or independent immune stimuli. Although initially identified by their ability to block CpG-induced immune activation, this class of suppressive ODN (typified by ODN A151) was subsequently shown to block multiple forms of immune stimulation and to be effective in the prevention and treatment of pathologic autoimmune diseases. Endotoxin-induced uveitis (EIU) is an established animal model of acute ocular inflammation. It is induced by either systemic or intravitreal administration of lipopolysaccharide (LPS). FMF is an autosomal recessive periodic fever disease characterized by recurrent, self-limiting, febrile, inflammatory attacks of the serosal membranes such as peritoneum, pleura, and synovia. FMF patients in clinical remission are reported to have increased baseline inflammation. Present study aims to demonstrate that the downregulatory effect of the suppressive DNA could prove benefit to alleviate the symptoms associated with i) LPS induced EIU in rabbit or murine models as model for local autoimmune disease and ii) Familial Mediterranean Fever a model for systemic autoinflammatory disease. Results from this research strongly implicated that A151 treated EIU induced animals downregulated IL6 and IL1b cytokine secretion or expression as well as chemokines such as or MIP3a, or iNOS levels. Our data suggest that FMF patient PBMCs to that of healthy donor`s blood were more responsive to TLR ligand stimulation and A151 incubation strongly reversed this activation and suppressed certain key cytokine/chemokine levels.