DNA β-Amyloid1-42 Trimer Immunization for Alzheimer Disease in a Wild-Type Mouse Model

Context DNA beta-amyloid(1-42) (A beta 42) trimer immunization was developed to produce specific T helper 2 cell (T(H)2)-type antibodies to provide an effective and safe therapy for Alzheimer disease (AD) by reducing elevated levels of A beta 42 peptide that occur in the brain of patients with AD. Objective To compare the immune response in wild-type mice after immunization with DNA A beta 42 trimer and A beta 42 peptide. Design and Intervention Wild-type mice received either 4 mu g of DNA A beta 42 trimer immunization administered with gene gun (n=8) or intraperitoneal injection of 100 mu g of human A beta 42 peptide with the adjuvant Quil A (n=8). Titers, epitope mapping, and isotypes of the A beta 42-specific antibodies were analyzed. Main Outcome Measures Antibody titers, mapping of binding sites (epitopes), isotype profiles of the A beta 42-specific antibodies, and T-cell activation. Results DNA A beta 42 trimer immunization resulted in antibody titers with a mean of 15 mu g per milliliter of plasma. The isotype profile of the antibodies differed markedly. A predominant IgG1 antibody response was found in the DNA-immunized mice, indicating a T(H)2 type of immune response (IgG1/IgG2a ratio of 10). The peptide-immunized mice showed a mixed T(H)1/T(H)2 immune response (IgG1/IgG2a ratio of 1) (P<.001). No increased T-cell proliferation was observed in the DNA-immunized mice (P=.03). Conclusion In this preliminary study in a wild-type mouse model, DNA A beta 42 trimer immunization protocol produced a T(H)2 immune response and appeared to have low potential to cause an inflammatory T-cell response. JAMA. 2009; 302(16):1796-1802 www.jama.com