Monoclonal antibodies to murine lipopolysaccharide (LIPS)-binding protein (LBP) protect mice from lethal endotoxemia by blocking either the binding of LPS to LBP or the presentation of LPS LBP complexes to CD14

Cellular responses to LPS, the major lipid component of the outer membrane of Gram-negative bacteria, are enhanced markedly by the LPS-binding protein (LBP), a, plasma protein that transfers LPS to the cell surface CD14 prese nt on cells of the myeloid lineage. LBP has been shown previously to potent iate the host response to LPS. However, experiments performed:in mice with a disruption of the LBP gene have yielded discordant results. Whereas one s tudy showed that LBP knockout mice were resistant to endotoxemia, another s tudy did not confirm an important role for LBP,in the response of mice chal lenged in vivo with low doses of LPS, Consequently, we generated rat mAbs t o murine LBP to investigate further the contribution of LBP in experimental endotoxemia, Three classes of mAbs were obtained, Class 1 mAbs blocked the binding of LPS to LBP; class 2 mAbs blocked the binding of LPS/LBP complex es to CD14; class 3 mAbs bound LBP but did not suppress LBP activity. In vi vo, class 1 and class 2 mAbs suppressed LPS-induced TNF production and prot ected mice from lethal endotoxemia, These results show that the neutralizat ion of LBP accomplished by blocking either the binding of LPS to LBP or the binding of LPS/LBP complexes to CD14 protects the host from LPS-induced to xicity, confirming that LBP is a critical component of innate immunity.