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* Department of Infectious Disease Immunology, Adjuvant Research, Statens Serum Institut, Copenhagen, Denmark; and
School of Biosciences, University of Birmingham, Edgbaston, Birmingham, United Kingdom
It is a long held belief that the strong immunostimulatory activity of the Mycobacterium bovis bacillus Calmette-Guérin vaccine and Freund’s complete adjuvant is due to specific mycobacterial cell envelope components, such as lipids and polysaccharides. Implicated mycobacterial lipids include, among others, the so-called cord factor or trehalose dimycolate, but limited information is available regarding the precise molecular nature of the stimulatory components responsible for the interaction with human APCs. In this regard, the majority of research aimed at identifying and characterizing individual immunostimulatory mycobacterial lipids has been performed in the murine system using bone marrow-derived dendritic cells. In this study, it is documented that potent immunostimulatory activity lies within the bacillus Calmette-Guérin nonpolar lipid class. This activity can be narrowed down to a remarkably simple monomycolyl glycerol (MMG) with the ability to stimulate human dendritic cells as assessed by enhanced expression of activation markers and the release of proinflammatory cytokines. A synthetic analog of MMG based on 32 carbons (C32) was found to exhibit comparable levels of immunostimulatory activities. Immunization of mice with the tuberculosis vaccine candidate, Ag85B-ESAT-6, in MMG or the synthetic analog using cationic liposomes as the delivery vehicle was found to give rise to a prominent Th1 response characterized by significant levels of IFN-
. Together, this development opens up the possibility of producing a novel class of chemically defined lipid adjuvants to enhance the activity of new vaccine formulations, directed against infectious agents including tuberculosis.
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 in part by a European Commission Contract LSHP-CT-2003-503367. G.S.B. has a James Bardrick Research Chair and a Royal Society Wolfson Research Merit Award. D.E.M. is a Leverhulme Emeritus Follow. G.S.B. and D.E.M. acknowledge support from the Medical Research Council (U.K.) and the Wellcome Trust.
2 C.S.A. and E.M.A. are co-first authors.
3 Address correspondence and reprint requests to Dr. Else Marie Agger, Department of Infectious Disease Immunology, Adjuvant Research, Statens Serum Institut, 2300 Copenhagen, Denmark. E-mail address: eag{at}ssi.dk
4 Abbreviations used in this paper: DC, dendritic cell; iDC, immature DC; BCG, bacillus Calmette-Guérin; PGL, phenolic glycolipid; TDM, trehalose dimycolate; MMG, monomycolyl glycerol; PPD, purified protein derivative; PGL, phenolic glycolipid; TAG, triacylglycerol; DDA, dimethyldioctadecyl ammonium; NMR, nuclear magnetic resonance.
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