Use of Immunomodulatory DNA for the Treatment of Diseases of Systemic Sepsis
Description
This invention is the discovery that within the intestinal mucosa, activation of the TLR9 immune receptor with de-methylated bacterial DNA (CPG-DNA) suppresses TLR4-mediated signaling. Suppression of TLR4 activity appears to significantly reduce the severity of necrotizing enterocolitis (NEC) and mucosal inflammation. TLR4 plays a critical role in the pathogenesis of NEC. This discovery would benefit patients with NEC or those at risk of developing NEC (essentially all premature infants) by acting as a selective immuno-modulator, thereby preventing the progression of the disease. This invention represents a novel strategy by which modulation of the innate immune system leads to attenuation of experimental NEC. TLR4 mediated signaling and cytokine release in enterocytes is attenuated by the TLR9 ligand, CpG-DNA in vitro and in vivo. TLR9 inhibits TLR4 signaling in enterocytes through effects on receptor localization.
