T-cell epitope-dependent immune response in inbred (C57BL/6J, SJL/J, and C3H/HeN) and transgenic P301S and Tg2576 mice

摘要

Alzheimer's disease is characterized by two pathological hallmarks, the intracellular deposition of hyperphosphorylated Tau protein and the extracellular deposition of Aβ_(1-40/42), both being targets for immunotherapy. This study evaluates the immunogenic properties of three AD-specific B-cell epitopes (Tau_(229-237)[pT231/pS235], pyroGluAβ_(3-8), and Aβ_(37/38-42/43)) linked to five foreign T-cell epitopes (MVFP, TT, TBC Ag85B, PvT19, and PvT53) by immunizing inbred C57BL/6J (H-2~b), SJL/J (H-2~(s2)), and C3H/HeN (H-2~k) mice. Two promising candidates with respect to MHC II restriction were selected, and two transgenic mouse models of AD, P301S (H-2~(b/k)) and Tg2576 (H-2~(b/s)) animals, were immunized with one B-cell epitope in combination with two T-cell epitopes. Responders displayed an enhanced immune response compared with wild-type animals, which supports the vaccine design and the vaccination strategy. The immune response was also characterized by specific IgG subtype titers, which revealed a strong polarization toward the humoral pathway for immunization of phospho-Tau, whereas for both Aβ vaccines, a mixed cellular/humoral pathway response was observed. Despite the diversity and unpredictability of the immunogenicity of the peptide vaccines, all three peptide vaccine formulations appear to be promising constructs for future evaluation of their therapeutic properties. Copyright ? 2013 European Peptide Society and John Wiley & Sons, Ltd. Immunogenic properties of three AD-specific B-cell epitopes (Tau_(229-237)[pT231/pS235], pyroGluAβ_(3-8), and Aβ_(37/38-42/43)) fused to five foreign T-cell epitopes (MVFP, TT, TBC Ag85B, PvT19, and PvT53) were evaluated by immunizing inbred C57BL/6J (H-2~b), SJL/J (H-2~(s2)), and C3H/HeN (H-2~k) mice. Afterwards, two transgenic mouse models of AD, P301S (H-2~(b/k)) and Tg2576 (H-2~(b/s)) animals, were immunized with the two most promising peptide vaccines. Immunization yielded high antigen-specific IgG titers with preferred IgG_1 in P301S mice and balanced IgG_1 and IgG_2 in Tg2576 mice.