Immune-stimulating complexes induce an IL-12-dependent cascade of innate immune responses

The development of subunit vaccines requires the use of adjuvants that act by stimulating components of the innate immune response, Immune-stimulating complexes (ISCOMS) containing the saponin adjuvant Quil A are potential va ccine vectors that induce a wide range of Ag-specific responses in vivo enc ompassing both humoral and CD4 and CDS cell-mediated immune responses. ISCO MS are active by both parenteral and mucosal routes, but the basis for thei r adjuvant properties is unknown. Here we have investigated the ability of ISCOMS to recruit and activate innate immune responses as measured in perit oneal exudate cells, The i.p. injection of ISCOMS induced intense local inf lammation, with early recruitment of neutrophils and mast cells followed by macrophages, dendritic cells, and lymphocytes. Many of the recruited cells had phenotypic evidence of activation and secreted a number of inflammator y mediators, including nitric oxide, reactive oxygen intermediates, IL-1, I L-6, IL-12 and IFN-gamma Of the factors that se investigated further only I L-12 appeared to be essential for the immunogenicity of ISCOMS, as IL-6-and inducible nitric oxide synthase knockout (KO) mice developed normal immune responses to OVA. in ISCOMS? whereas these responses were markedly reduced in IL-12KO mice,The recruitment of peritoneal exudate cells following an i njection of ISCOMS was impaired in IL-12KO mice, indicating a role for IL-1 2 in establishing the proinflammatory cascade. Thus, ISCOMS prime Ag-specif ic immune responses at least in part by activating IL-12-dependent aspects of the innate immune system.