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* Department of Infectious Disease Immunology, Adjuvant Research, Statens Serum Institut, Copenhagen, Denmark;
School of Biosciences, University of Birmingham, Edgbaston, Birmingham, United Kingdom;
Mikrobiologisches Institut, Universitätsklinikum Erlangen, Erlangen, Germany; and
Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Munchen, Germany
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-
, TNF-
, 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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the European Commission (contract no. LSHP-CT-2003-503367). G.S.B. has a James Bardrick Research Chair and a Royal Society Wolfson Research Merit Award, and D.E.M. was a Leverhulme Emeritus Fellow; both acknowledge support from the Medical Research Council (U.K.) and the Wellcome Trust.
2 Address correspondence and reprint requests to Dr. Else Marie Agger, Department of Infectious Disease Immunology, Adjuvant Research, Statens Serum Institut, 5 Artillerivej, DK-2300 Copenhagen S, Denmark. E-mail address: eag{at}ssi.dk
3 Abbreviations used in this paper: TB, tuberculosis; BCG, bacillus Calmette-Guérin; BMDC, bone marrow dendritic cell; C18 MAG, C18 mono-acyl glycerol analog; DC, dendritic cell; DDA, dimethyldioctadecylammonium; FCA, Freund’s complete adjuvant; MMG, monomycoloyl glycerol; NMR, nuclear magnetic resonance; PDIM, phthiocerol dimycocerosate; PGL, phenolic glycolipid; PIM, phosphatidylinositol mannoside; TAG, triacylglycerol; TDM, trehalose dimycolate.
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