Modulation of the humoral and cellular immune response in Abeta immunotherapy by the adjuvants monophosphoryl lipid A (MPL), cholera toxin B subunit (CTB) and E. coli enterotoxin LT(R192G).
Abeta vaccination or passive transfer of human-specific anti-Abeta antibodies are approaches under investigation to prevent and/or treat Alzheimer's disease (AD). Successful active Abeta vaccination requires a strong and safe adjuvant to induce anti-Abeta 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 Abeta1-40/42 as a common immunogen in wildtype B6D2F1 mice. Subcutaneous (s.c.) administration with MPL/TDM resulted in anti-Abeta antibodies levels up to four times higher compared to s.c. LT(R192G). Using MPL/TDM, the anti-Abeta antibodies induced were mainly IgG2b, IgG1 and lower levels of IgG2a and IgM, with a moderate splenocyte proliferation and IFN-gamma production in vitro upon stimulation with Abeta1-40/42. LT(R192G), previously shown by us to induce robust titers of anti-Abeta antibodies, generated predominantly IgG2b and IgG1 anti-Abeta antibodies with very low splenocyte proliferation and IFN-gamma production. Weekly intranasal (i.n.) administration over 11 weeks of Abeta40/42 with CTB induced only moderate levels of antibodies. All immunogens generated antibodies that recognized mainly the Abeta1-7 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 Abeta40/42 and may aid in the design of Abeta immunotherapy.
Maier
Marcel
M
Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Seabrook
Timothy J
TJ
Lemere
Cynthia A
CA
D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000544:Alzheimer Disease / Q000276:immunology / Q000517:prevention & control*; D023582:Alzheimer Vaccines / Q000008:administration & dosage*; D016229:Amyloid beta-Peptides / Q000276:immunology*; D000818:Animals; D000917:Antibody Formation / Q000187:drug effects; D001427:Bacterial Toxins / Q000008:administration & dosage / Q000276:immunology; D002772:Cholera Toxin / Q000008:administration & dosage / Q000276:immunology; D004768:Enterotoxins / Q000008:administration & dosage / Q000276:immunology; D004926:Escherichia coli / Q000276:immunology; D029968:Escherichia coli Proteins / Q000008:administration & dosage / Q000276:immunology; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects; D007167:Immunotherapy; D008050:Lipid A / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000276:immunology; D008297:Male; D051379:Mice
D000276:Adjuvants, Immunologic; D023582:Alzheimer Vaccines; D016229:Amyloid beta-Peptides; D001427:Bacterial Toxins; D004768:Enterotoxins; D029968:Escherichia coli Proteins; D008050:Lipid A; D002772:Cholera Toxin; C027538:heat-labile enterotoxin, E coli; C048436:monophosphoryl lipid A