Therapeutic potential of the bactericidal/permeability-increasing protein

Innate immune mechanisms respond rapidly to bacterial infection. A key cellular component of the innate immune response is the neutrophil, whose cytoplasmic granules contain a variety of antimicrobial proteins and peptides. Among these is the bactericidal/permeability-increasing protein (BPI), a cationic 55 kDa protein whose selective anti-infective action against Gram-negative bacteria is based on its high (nM) affinity for lipopolysaccharide (LPS, or "endotoxin"). Binding of BPI to Gram-negative bacteria results in growth inhibition, serves as an opsonin that enhances phagocytosis of bacteria and inhibits bacteria-induced inflammatory responses by blocking the interaction of LPS with host pro-inflammatory pathways. Expression of BPI appears to be developmentally regulated as human newborns apparently have lower neutrophil BPI levels than adults. BPI expression has also recently been demonstrated in human epithelial cells where it appears to be inducible by endogenous anti-inflammatory lipids (lipoxins). BPI's potent anti-endotoxic activity against a broad range of Gram-negative bacterial pathogens is manifest in biological fluids and renders it an attractive template for pharmaceutical development. Indeed, rBPI(21), an active recombinant protein derived from human BPI, has proven safe in Phase I human trials, shown promise in Phase II trials and has recently completed a Phase III trial for severe meningococcaemia with apparent benefit. Identification and evaluation of additional disease entities characterised by Gram-negative bacteraemia and/or endotoxaemia as possible targets for BPI therapy continues.