title: Adjuvant modulation of the cytokine balance in Mycobacterium tuberculosis subunit vaccines; immunity, pathology and protection.
abstract: It is known that protection against tuberculosis is mediated primarily by T helper type 1 (Th1) cells but the influence of the Th1/Th2 balance of a vaccination response on the subsequent protection and pathology during infection has not been studied in detail. We designed a panel of Ag85B-ESAT-6 subunit vaccines based on adjuvants with different Th1/Th2-promoting activities and studied cellular responses, bacterial replication and pathology in the lungs of mice infected with Mycobacterium tuberculosis. All vaccines induced cell-mediated and humoral responses but with markedly different interferon-gamma : interleukin-5 (IFN-gamma : IL-5) and immunoglobulin G1 (IgG1) : IgG2 ratios. The vaccines promoted different levels of control of bacterial replication with the most efficient protection being exerted by cationic liposomes containing monophosphoryl lipid A and low to completely absent immunity with conventional aluminium. The level of protection correlated with the amount of IFN-gamma produced in response to the vaccine whereas there was no inverse correlation with the level of IL-5. Characterizing a protective response was an accelerated recruitment of IL-17 and IFN-gamma-producing lymphocytes resulting in the early formation of granulomas containing clustered inducible nitric oxide synthase-activated macrophages. In comparison, non-protected mice exhibited a different inflammatory infiltrate rich in neutrophil granulocytes. This study indicates that the adjuvant component of a tuberculosis vaccine may be crucial in determining the kinetics by which effective granulomas, pivotal in controlling bacterial growth, are formed.
authors.affiliation: Department of Infectious Disease Immunology, Statens Serum Institut, Copenhagen, Denmark. eag@ssi.dk
authors.forename: Else Marie
authors.initials: EM
authors.lastname: Agger
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Cassidy
authors.forename: Joseph
authors.initials: J
authors.lastname: Brady
authors.forename: Karen S
authors.initials: KS
authors.lastname: Korsholm
authors.forename: Carina
authors.initials: C
authors.lastname: Vingsbo-Lundberg
authors.forename: Peter
authors.initials: P
authors.lastname: Andersen
mesh_terms: D000276:Adjuvants, Immunologic; D000818:Animals; D002478:Cells, Cultured; D005260:Female; D006099:Granuloma / Q000276:immunology / Q000382:microbiology; D007114:Immunization / Q000379:methods; D007371:Interferon-gamma / Q000096:biosynthesis; D008168:Lung / Q000276:immunology / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009169:Mycobacterium tuberculosis / Q000276:immunology / Q000302:isolation & purification; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D032581:Tuberculosis Vaccines / Q000276:immunology*; D014397:Tuberculosis, Pulmonary / Q000276:immunology / Q000382:microbiology / Q000473:pathology / Q000517:prevention & control*; D022223:Vaccines, Subunit / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D032581:Tuberculosis Vaccines; D022223:Vaccines, Subunit; D007371:Interferon-gamma