Human monoclonal antibodies against Pseudomonas aeruginosa lipopolysaccharide derived from transgenic mice containing megabase human immunoglobulin loci are opsonic and protective against fatal pseudomonas sepsis. Infect Immun 2001 Apr;69(4):2223-9
Date
03/20/2001Pubmed ID
11254577Pubmed Central ID
PMC98149DOI
10.1128/IAI.69.4.2223-2229.2001Scopus ID
2-s2.0-0035077840 (requires institutional sign-in at Scopus site) 45 CitationsAbstract
Pseudomonas aeruginosa is a significant human pathogen, and no vaccine is commercially available. Passive antibody prophylaxis using monoclonal antibodies (MAb) against protective P. aeruginosa epitopes is an alternative strategy for preventing P. aeruginosa infection, but mouse MAb are not suitable for use in humans. Polyclonal human antibodies from multiple donors have variable antibody titers, and human MAb are difficult to make. We used immunoglobulin-inactivated transgenic mice reconstituted with megabase-size human immunoglobulin loci to generate a human MAb against the polysaccharide (PS) portion of the lipopolysaccharide O side chain of a common pathogenic serogroup of P. aeruginosa, 06ad. The anti-PS human immunoglobulin G2 MAb made from mice immunized with heat-killed P. aeruginosa was specific for serogroup 06ad pseudomonas. The MAb was highly opsonic for the uptake and killing of P. aeruginosa by human polymorphonuclear leukocytes in the presence of human complement. In addition, 25 microg of the MAb protected 100% of neutropenic mice from fatal P. aeruginosa sepsis. DNA sequence analysis of the genes encoding the MAb revealed V(H)3 and Vkappa2/A2 variable-region genes, similar to variable-region genes in humans immunized with bacterial PS and associated with high-avidity anti-PS antibodies. We conclude that human MAb to P. aeruginosa made in these transgenic mice are highly protective and that these mice mimic the antibody response seen in humans immunized with T-cell-independent antigens such as bacterial PS.
Author List
Hemachandra S, Kamboj K, Copfer J, Pier G, Green LL, Schreiber JRMESH terms used to index this publication - Major topics in bold
AnimalsAntibodies, Bacterial
Antibodies, Monoclonal
Bacteremia
Chromosome Mapping
Humans
Immunization
Lipopolysaccharides
Mice
Mice, Transgenic
Neutrophils
Phagocytosis
Pseudomonas Infections
Pseudomonas aeruginosa
