RESUMO
Immunotherapeutic approaches to treating Alzheimer's disease (AD) using vaccination strategies must overcome the obstacle of achieving adequate responses to vaccination in the elderly. Here we demonstrate for the first time that application of the Escherichia coli heat-labile enterotoxin adjuvant-laden immunostimulatory patches (LT-IS) dramatically enhances the onset and magnitude of immune responses to DNA- and protein-based vaccines for Alzheimer's disease following intradermal immunization via gene gun and conventional needles, respectively. Our studies suggest that the immune activation mediated by LT-IS offers improved potency for generating AD-specific vaccination responses that should be investigated as an adjuvant in the clinical arena.
Assuntos
Adjuvantes Imunológicos/administração & dosagem , Vacinas contra Alzheimer/imunologia , Toxinas Bacterianas/administração & dosagem , Enterotoxinas/administração & dosagem , Proteínas de Escherichia coli/administração & dosagem , Vacinação/métodos , Peptídeos beta-Amiloides/imunologia , Animais , Anticorpos Antivirais/sangue , Toxinas Bacterianas/imunologia , Modelos Animais de Doenças , Enterotoxinas/imunologia , Ensaio de Imunoadsorção Enzimática , Epitopos de Linfócito B/imunologia , Epitopos de Linfócito T/imunologia , Escherichia coli , Proteínas de Escherichia coli/imunologia , Feminino , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Adesivo Transdérmico , Vacinas de DNA/imunologiaRESUMO
The Alzheimer's disease (AD) process is understood to involve the accumulation of amyloid plaques and tau tangles in the brain. However, attempts at targeting the main culprits, neurotoxic Aß peptides, have thus far proven unsuccessful for improving cognitive function. Recent clinical trials with passively administrated anti-Aß antibodies failed to slow cognitive decline in mild to moderate AD patients, but suggest that an immunotherapeutic approach could be effective in patients with mild AD. Using an AD mouse model (Tg2576), we tested the immunogenicity (cellular and humoral immune responses) and efficacy (AD-like pathology) of clinical grade Lu AF20513 vaccine. We found that Lu AF20513 induces robust "non-self" T-cell responses and the production of anti-Aß antibodies that reduce AD-like pathology in the brains of Tg2576 mice without inducing microglial activation and enhancing astrocytosis or cerebral amyloid angiopathy. A single immunization with Lu AF20513 induced strong humoral immunity in mice with preexisting memory T-helper cells. In addition, Lu AF20513 induced strong humoral responses in guinea pigs and monkeys. These data support the translation of Lu AF20513 to the clinical setting with the aims of: (1) inducing therapeutically potent anti-Aß antibody responses in patients with mild AD, particularly if they have memory T-helper cells generated after immunizations with conventional tetanus toxoid vaccine, and (2) preventing pathological autoreactive T-cell responses.