title: Novel generation mycobacterial adjuvant based on liposome-encapsulated monomycoloyl glycerol from Mycobacterium bovis bacillus Calmette-Guérin.
abstract: The immunostimulatory activity of lipids associated with the mycobacterial cell wall has been recognized for several decades and exploited in a large variety of different adjuvant preparations. Previously, we have shown that a mycobacterial lipid extract from Mycobacterium bovis bacillus Calmette-Guérin delivered in cationic liposomes was a particular efficient Th1-inducing adjuvant formulation effective against tuberculosis. Herein, we have dissected the adjuvant activity of the bacillus Calmette-Guérin lipid extract showing that the majority of the activity was attributable to the apolar lipids and more specifically to a single lipid, monomycoloyl glycerol (MMG), previously also shown to stimulate human dendritic cells. Delivered in cationic liposomes, MMG induced the most prominent Th1-biased immune response that provided significant protection against tuberculosis. Importantly, a simple synthetic analog of MMG, based on a 32 carbon mycolic acid, was found to give rise to comparable high Th1-biased responses with a major representation of polyfunctional CD4 T cells coexpressing IFN-gamma, TNF-alpha, and IL-2. Furthermore, comparable activity was shown by an even simpler monoacyl glycerol analog, based on octadecanoic acid. The use of these synthetic analogs of MMG represents a promising new strategy for exploiting the immunostimulatory activity and adjuvant potential of components from the mycobacterial cell wall without the associated toxicity issues observed with complex mycobacterial preparations.
authors.affiliation: Department of Infectious Disease Immunology, Adjuvant Research, Statens Serum Institut, Copenhagen, Denmark;
authors.forename: Claire A Swetman
authors.initials: CA
authors.lastname: Andersen
authors.forename: Ida
authors.initials: I
authors.lastname: Rosenkrands
authors.forename: Anja W
authors.initials: AW
authors.lastname: Olsen
authors.forename: Pernille
authors.initials: P
authors.lastname: Nordly
authors.forename: Dennis
authors.initials: D
authors.lastname: Christensen
authors.forename: Roland
authors.initials: R
authors.lastname: Lang
authors.forename: Carsten
authors.initials: C
authors.lastname: Kirschning
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Gomes
authors.forename: Veemal
authors.initials: V
authors.lastname: Bhowruth
authors.forename: David E
authors.initials: DE
authors.lastname: Minnikin
authors.forename: Gurdyal S
authors.initials: GS
authors.lastname: Besra
authors.forename: Frank
authors.initials: F
authors.lastname: Follmann
authors.forename: Peter
authors.initials: P
authors.lastname: Andersen
authors.forename: Else Marie
authors.initials: EM
authors.lastname: Agger
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000818:Animals; D001500:BCG Vaccine / Q000008:administration & dosage* / Q000276:immunology*; D002478:Cells, Cultured; D005260:Female; D005990:Glycerol / Q000008:administration & dosage / Q000276:immunology; D008081:Liposomes / Q000008:administration & dosage / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D050178:Monoglycerides / Q000008:administration & dosage* / Q000276:immunology*; D009163:Mycobacterium bovis / Q000276:immunology*; D009171:Mycolic Acids / Q000008:administration & dosage / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D001500:BCG Vaccine; D008081:Liposomes; D050178:Monoglycerides; D009171:Mycolic Acids; C543328:monomycoloyl glycerol; D005990:Glycerol