Monophosphoryl lipid A behaves as a T-cell-independent type 1 carrier for hapten-specific antibody responses in mice

Abstract

It is known that the lipopolysaccharide (LPS) of gram-negative bacteria, in addition to being a potent adjuvant, is an effective carrier for covalently associated haptens. However, the toxic nature of most forms of LPS precludes their use as adjuvants or carriers for human vaccines. 4-Monophosphoryl lipid A (MLA), a derivative of LPS with attenuated toxicity, is currently being tested in humans as an immunological adjuvant. In this study, MLA was tested for its ability to function as a carrier for a small hapten, the trinitrophenyl group (TNP). MLA was first modified by addition of 6-aminocaproic acid to the 6 position of the disaccharide backbone (Cap-MLA). TNP was then attached to Cap-MLA via the free amino group, yielding TNP-Cap-MLA. Immunization of normal mice with TNP-Cap-MLA resulted in high-titer anti-TNP responses of immunoglobulin M and all immunoglobulin G subclasses. Furthermore MLA, like other T-cell-independent type 1 (TI-1) carriers, induced responses in athymic and X-linked immunodeficient mice. In all cases, immunization with either MLA alone or TNP-Cap plus MLA failed to induce measurable anti-TNP antibodies of any isotype, indicating that covalent association of MLA and hapten was necessary for MLA's carrier activity to be manifested. These properties of MLA make it a potential candidate as a carrier for vaccine subunit components, such as small peptides, especially for situations in which T-cell help is impaired, as occurs following human immunodeficiency virus type 1 infection.

Combination vaccines for the treatment of grass pollen allergy consisting of genetically engineered hybrid molecules with increased immunogenicity

“…Because our antigen preparations represented pure proteins, we consider T cell‐independent carrier effects as were described for monophosphoryl lipid A (MLA) as a second, rather unlikely possibility for their increased immunogenicity (50).…”

Microbial products in allergy prevention and therapy

“…In an animal model, LPS exposure can prevent allergen sensitization and abolish the late phase inflammatory response in already sensitized mice (73). MPL has similar potent adjuvant properties of LPS (71, 74), but is less toxic, as it has a reduced ability (relative to LPS) to induce proinflammatory cytokines (75). Indeed, in vitro MPL can induce in mouse peritoneal macrophages higher levels of IL‐10, the anti‐inflammtory cytokine which reduces the production of proinflammatory cytokines (75).…”

“…It was hypothesised that environmental LPS or endotoxin exposure would stimulate in humans TH1 immune responses and that this would protect against the development of atopy and asthma (79, 80). LPS exerts also severe endotoxic effects which limit its potential use as a therapeutic agent (74, 81). On this basis, LPS derivatives that could maintain immunostimulating properties of LPS but not its toxicity were tested in vivo as modulators of specific immune responses, including those against allergens (72, 82).…”

Lipopolysaccharide and monophosphoryl lipid A differentially regulate interleukin-12, gamma interferon, and interleukin-10 mRNA production in murine macrophages

“…Monophosphoryl lipid A (MPL) is a detoxified derivative of LPS that lacks many of the endotoxic properties of LPS yet retains both its adjuvant and immunostimulatory activities (2,9,34,45,61). MPL, commercially available as MPL immunostimulant, was developed both as an adjuvant for human vaccines and as a prophylactic drug for septic shock (reviewed in reference 50 and 62).…”