Attachment of monophosphoryl lipid A (MPL) to cells and liposomes augments antibody response to membrane-bound gangliosides.

Abstract

Antibodies to gangliosides are found in low levels in normal individuals, and attempts to augment their production have had limited success. Murine studies suggest that the antibody response to membrane-bound cryptic antigens, such as phospholipids and gangliosides, can be induced and augmented by attaching lipid A to membranes. Therefore, we assessed the ability of monophosphoryl lipid A, a non-toxic derivative of lipid A, to augment antibody response against membrane-associated gangliosides. Anti-ganglioside antibodies were IgM after the first and second immunizations; in contrast, anti-phospholipid antibodies were IgM after the first immunization and IgG after the second immunization. Mice (BALB/c) immunized with MPL-attached human cells as well as mice (C57BL/6J) immunized with MPL-attached syngeneic tumor cells (B16 melanoma) produced a significant IgM response. Mice (C57BL/6J) immunized with MPL-attached liposomes containing GM3 developed significantly higher IgM responses than those immunized with purified gangliosides, MPL or MPL-free B16 cells. However, the antibody response after immunization with MPL-GM3-liposomes is similar to that after immunization with MPL-attached tumor cells, even though the MPL-liposomes contained a 27-fold higher level of gangliosides than the tumor cells. Our results emphasize that co-expression of MPL with membrane-bound gangliosides is necessary to augment the anti-ganglioside antibody response. These findings may shed light on the elevated titers of anti-ganglioside IgM antibodies found in patients with motor neuron diseases, various neuropathies and classical ALS, and are relevant to clearance of circulating immunosuppressive gangliosides in cancer patients.