Suppressive oligodeoxynucleotides as a TLR antagonist : efforts to treat autoimmune diseases
Author(s)
Advisor
Gürsel, İhsanDate
2007Publisher
Bilkent University
Language
English
Type
ThesisItem Usage Stats
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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.