Modulation of the humoral and cellular immune response in Aβ immunotherapy by the adjuvants monophosphoryl lipid A (MPL), cholera toxin B subunit (CTB) and E. coli enterotoxin LT(R192G)

Abstract

Aβ vaccination or passive transfer of human-specific anti-Aβ antibodies are approaches under investigation to prevent and/or treat Alzheimer's disease (AD). Successful active Aβ vaccination requires a strong and safe adjuvant to induce anti-Aβ antibody formation. We compared the adjuvants monophosphoryl lipid A (MPL)/trehalose dicorynomycolate (TDM), cholera toxin B subunit (CTB) and Escherichia coli heat-labile enterotoxin LT(R192G) for their ability to induce a humoral and cellular immune reaction, using fibrillar Aβ1–40/42 as a common immunogen in wildtype B6D2F1 mice. Subcutaneous (s.c.) administration with MPL/TDM resulted in anti-Aβ antibodies levels up to four times higher compared to s.c. LT(R192G). Using MPL/TDM, the anti-Aβ antibodies induced were mainly IgG2b, IgG1 and lower levels of IgG2a and IgM, with a moderate splenocyte proliferation and IFN-γ production in vitro upon stimulation with Aβ1–40/42. LT(R192G), previously shown by us to induce robust titers of anti-Aβ antibodies, generated predominantly IgG2b and IgG1 anti-Aβ antibodies with very low splenocyte proliferation and IFN-γ production. Weekly intranasal (i.n.) administration over 11 weeks of Aβ40/42 with CTB induced only moderate levels of antibodies. All immunogens generated antibodies that recognized mainly the Aβ1–7 epitope and specifically detected amyloid plaques on AD brain sections. In conclusion, MPL/TDM, in addition to LT(R192G), is an effective adjuvant when combined with Aβ40/42 and may aid in the design of Aβ immunotherapy.