Here we describe development of an extracorporeal hemoadsorption device for
sepsis therapy that employs commercially available
polysulfone or
polyethersulfone hollow fiber filters similar to those used clinically for
hemodialysis, covalently coated with a genetically engineered form of the human
opsonin Mannose Binding Lectin linked to an Fc domain (FcMBL) that can cleanse a broad range of pathogens and
endotoxin from flowing blood without having to first determine their identity. When tested with human whole blood in vitro, the FcMBL hemoadsorption filter (FcMBL-HF) produced efficient (90-99%) removal of Gram negative (Escherichia coli) and positive (Staphylococcus aureus) bacteria, fungi (Candida albicans) and
lipopolysaccharide (LPS)-
endotoxin. When tested in rats, extracorporeal
therapy with the FcMBL-HF device reduced circulating pathogen and
endotoxin levels by more than 99%, and prevented pathogen engraftment and inflammatory cell recruitment in the spleen, lung, liver and kidney when compared to controls. Studies in rats revealed that treatment with bacteriocidal
antibiotics resulted in a major increase in the release of microbial fragments or '
pathogen-associated molecular patterns' (
PAMPs) in vivo, and that these
PAMPs were efficiently removed from blood within 2 h using the FcMBL-HF; in contrast, they remained at high levels in animals treated with
antibiotics alone. Importantly, cleansing of
PAMPs from the blood of
antibiotic-treated animals with the FcMBL-hemoadsorbent device resulted in reduced organ pathogen and
endotoxin loads, suppressed inflammatory responses, and resulted in more stable vital signs compared to treatment with
antibiotics alone. As
PAMPs trigger the
cytokine cascades that lead to development of
systemic inflammatory response syndrome and contribute to
septic shock and death, co-administration of FcMBL-hemoadsorption with
antibiotics could offer a more effective approach to
sepsis therapy.