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Gene Vaccination to Bias the Immune Response to Amyloid- Peptide as Therapy for Alzheimer Disease

Baoxi Qu, MD; Roger N. Rosenberg, MD; Liping Li, MD; Philip J. Boyer, MD, PhD; Stephen A. Johnston, PhD

Arch Neurol. 2004;61:1859-1864.

Background  The amyloid- (A) peptide has a central role in the neurodegeneration of Alzheimer disease (AD). Immunization of AD transgenic mice with A_1-42 (A₄₂) peptide reduces both the spatial memory impairments and AD-like neuropathologic changes in these mice. Therapeutic immunization with A in patients with AD was shown to be effective in reducing A deposition, but studies were discontinued owing to the development of an autoimmune, cell-mediated meningoencephalitis. We hypothesized that gene vaccination could be used to generate an immune response to A₄₂ that produced antibody response but avoided an adverse cell-mediated immune effect.

Objective  To develop an effective genetic immunization approach for treatment and prevention of AD without causing an autoimmune, cell-mediated meningoencephalitis.

Methods  Mice were vaccinated with a plasmid that encodes A₄₂, administered by gene gun. The immune response of the mice to A₄₂ was monitored by measurement of (1) antibody levels by enzyme-linked immunosorbent assay (ELISA) and Western blot and (2) A₄₂-specific T-cell response as measured by interferon- enzyme-linked immunospot (ELISPOT) assay.

Results  Gene-gun delivery of the mouse A₄₂ dimer gene induced significant humoral immune responses in BALB/c wild-type mice after 3 vaccinations in 10-day intervals. All 3 mice in the treated group showed significant humoral immune responses. The ELISPOT assay for interferon- release with mouse A₄₂ peptide and A_9-18 showed no evident cytotoxic T-lymphocyte response. We further tested the responses of wild-type BALB/c mice to the monomer A₄₂ gene vaccine. Western blot evaluation showed both human and mouse A monomer gene vaccine elicited detectable humoral immune responses. We also introduced the human A₄₂ monomer gene vaccine into AD double transgenic mice APPswe/PSEN1(A246E). Mice were vaccinated with plasmids that encode A_1-42 and A_1-16, or with plasmid without the A gene. Treated mice showed significant humoral immune responses as demonstrated by ELISA and by Western blot. These mice also showed no significant cellular immune response as tested by ELISPOT. One of the treated mice was killed at 7 months of age for histological observations, and scattered amyloid plaques were noted in all layers of the cerebral cortex and in the hippocampus in both A₄₂- and control-vaccinated mice. No definite difference was discerned between the experimental and control animals.

Conclusions  Gene-gun–administered genetic immunization with the A₄₂ gene in wild-type BALB/c and AD transgenic mice can effectively elicit humoral immune responses without a significant T-cell–mediated immune response to the A peptide. This immunotherapeutic approach could provide an alternative active immunization method for therapy and prevention of AD.

Author Affiliations: Center for Biomedical Inventions, Department of Internal Medicine (Drs Qu, Li, and Johnston), Alzheimer’s Disease Center, Department of Neurology (Dr Rosenberg), and the Departments of Pathology (Dr Boyer) and Microbiology (Dr Johnston), University Texas Southwestern Medical Center at Dallas.

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