Production of protective human antipneumococcal antibodies by transgenic mice with human immunoglobulin loci.
Infections with Streptococcus pneumoniae remain a significant cause of morbidity and mortality. To gain insight into structure-function relationships for human antibodies to pneumococcal capsular polysaccharide (PPS), we studied the response of transgenic mice reconstituted with human immunoglobulin loci, XenoMouse, to PPS antigens in a pneumococcal vaccine. Enzyme-linked immunosorbent assays of sera from mice vaccinated with a 23-valent pneumococcal vaccine revealed that they produced serotype-specific human antibodies, with the greatest response being to the PPS of serotype 3 (PPS 3). Molecular sequence analysis of three monoclonal antibodies (MAbs) to PPS 3 generated from lymphoid cells from mice vaccinated with a 23-valent pneumococcal vaccine or a PPS 3-bovine serum albumin conjugate revealed that they all used heavy-chain immunoglobulin genes from the V(H)3 family, two expressed light chain genes from the human Vkappa1 family, and one expressed a mouse lambda light chain. The protective efficacy of the two MAbs was examined in mice. A 10-microgram dose of both, and a 1-microgram dose of one, significantly prolonged survival from a lethal serotype 3 infection in CBA/N mice. Our data show that XenoMouse mice produced protective, serotype-specific human antibodies to PPS 3, and they lend support to the proposal that these animals represent a useful model to study the human antibody response to PPS antigens.
Russell
N D
ND
Department of Medicine, Division of Infectious Disease, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Corvalan
J R
JR
Gallo
M L
ML
Davis
C G
CG
Pirofski
L a
La
D000818:Animals; D000907:Antibodies, Bacterial / Q000096:biosynthesis*; D000911:Antibodies, Monoclonal / Q000276:immunology; D000918:Antibody Specificity; D003167:Complement Activation; D022801:Complementarity Determining Regions; D005260:Female; D005803:Genes, Immunoglobulin; D006801:Humans; D006825:Hybridomas / Q000276:immunology; D007135:Immunoglobulin Variable Region / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D011135:Polysaccharides, Bacterial / Q000276:immunology*; D013296:Streptococcus pneumoniae / Q000276:immunology*; D013329:Structure-Activity Relationship; D013997:Time Factors; D014611:Vaccination
D000907:Antibodies, Bacterial; D000911:Antibodies, Monoclonal; D022801:Complementarity Determining Regions; D007135:Immunoglobulin Variable Region; D011135:Polysaccharides, Bacterial; C047620:pneumococcal polysaccharide, type II