Durable elimination of high affinity, T cell-dependent antibodies by low molecular weight antigen arrays in vivo.
Ongoing Ab responses to a T cell-dependent Ag can be suppressed in hyperimmune animals by exogenous, multivalent Ag arrays. The pharmacologic basis for this suppression was studied by varying the molecular mass, ligand valence, and dose of Ag arrays, and then determining their efficacy, pharmacokinetics, and tissue distribution. Arrays ranging in molecular mass from 30 to 500 kDa caused initial clearance of specific serum Abs, but only the smaller arrays caused persistent suppression despite their relatively lower binding avidity and shorter retention in vivo. Suppression by the smaller arrays at lower doses was biphasic, implying two distinct modes of Ab elimination. High affinity IgG was eliminated preferentially, as shown by calibrated variable ligand-density ELISA. Suppressive arrays were localized discretely in the splenic germinal centers of hyperimmune animals. These results indicate that Ag array mass, ligand valence, and dose all play critical roles, and histologic compartmentalization may also be a pertinent parameter, in determining suppressive efficacy in vivo.
D000818:Animals; D000906:Antibodies / Q000097:blood*; D000915:Antibody Affinity / Q000187:drug effects* / Q000276:immunology; D000941:Antigens / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology*; D001666:Binding Sites, Antibody / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006207:Half-Life; D007114:Immunization; D007074:Immunoglobulin G / Q000032:analysis; D007165:Immunosuppression Therapy / Q000379:methods*; D051379:Mice; D008815:Mice, Inbred Strains; D008970:Molecular Weight; D009928:Organ Specificity; D010599:Pharmacokinetics; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology
D000906:Antibodies; D000941:Antigens; D007074:Immunoglobulin G