Anti-HMGB1 Antibodies and Alpha-7 Agonists as Experimental Therapeutics as BW Countermeasures

摘要

Biological warfare agents cause lethality by activating systemic inflammation. After infection, cells of the innate immune system, including macrophages release soluble factors like TNF, HMGB1 in addition to other proinflammatory cytokines that cause shock and widespread tissue injury. We originally identified a cytokine role for HMGB1, a protein known previously as a transcription factor, and have since focused our efforts on studying the role of this mediator in the pathogenesis of severe sepsis. We discovered that high levels of HMGB1 are produced in humans and animals with sepsis. Administration of HMGB1 to experimental animals causes lethal organ damage. We have developed and tested monoclonal antibodies that specifically neutralize HMGB1 bioactivity in vitro. With DARPA support we have discovered that inhibition of HMGB1 activity attenuates lethality in live animals with infection. In addition to HMGB1, we have extended our studies in understanding the role of an acetylcholine receptor subunit, known as alpha-7. Alpha-7 receptor is expressed on the macrophages and plays an important role in the innate immune system by controlling activation of macrophages. Alpha-7 receptor agonists like acetylcholine and nicotine, inhibit HMGB1 release by macrophages, thus controlling the innate immune response. With DARPA support, we have proved the effectiveness of anti-inflammatory agents designed to activate the alpha-7 subunit and modulate the lethal immune response.