Adjuvant modulation of the cytokine balance in Mycobacterium tuberculosis subunit vaccines; immunity, pathology and protection.
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.
Agger
Else Marie
EM
Department of Infectious Disease Immunology, Statens Serum Institut, Copenhagen, Denmark. eag@ssi.dk
Cassidy
Joseph P
JP
Brady
Joseph
J
Korsholm
Karen S
KS
Vingsbo-Lundberg
Carina
C
Andersen
Peter
P
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
D000276:Adjuvants, Immunologic; D032581:Tuberculosis Vaccines; D022223:Vaccines, Subunit; D007371:Interferon-gamma