Risk Factors Associated With β-Amyloid(1-42) Immunotherapy in Preimmunization Gene Expression Patterns of Blood Cells

Abstract

Background: A phase 2a, double-blind, placebocontrolled, multicenter study was conducted to evaluate safety, tolerability, and pilot efficacy of immunization with ␤-amyloid (1-42) in patients with Alzheimer disease. Six immunizations were planned but were halted when meningoencephalitis was recognized as an adverse event in 6% of immunized patients. Objective: To identify biomarkers associated with both the risk of meningoencephalitis and antibody responsiveness. Participants: One hundred fifty-three patients with mild to moderate Alzheimer disease. Main Outcome Measure: Association between response to immunization and preimmunization expression levels of 8239 messenger RNA transcripts expressed in peripheral blood mononuclear cells that had been collected at the screening visit. Results: Expression patterns of genes related to apoptosis and proinflammatory pathways (tumor necrosis factor pathway in particular) were identified as biomarkers of risk for the development of meningoencephalitis. Expression patterns of genes related to protein synthesis, protein trafficking, DNA recombination, DNA repair, and cell cycle were strongly associated with IgG response to immunization. Conclusions: Candidate biomarkers associated with risk of immunotherapy-related meningoencephalitis were detected in blood collected prior to treatment. In addition, a different set of biomarkers were identified that were associated with the desired outcome of IgG response.

Short Amyloid-β (Aβ) Immunogens Reduce Cerebral Aβ Load and Learning Deficits in an Alzheimer's Disease Mouse Model in the Absence of an Aβ-Specific Cellular Immune Response

“…The versatility of the T1 Th-cell epitope with different mouse MHC class II loci and different species make these immunogens an attractive candidate for additional studies in particular with other mouse strains or species. A recent publication analyzing gene expression profiles of patients from an AN-1792 immunization trial suggest reduced abilities to mount an effective immune response against A␤, mainly because of the advanced age of the patients (O'Toole et al, 2005). Therefore, activation of the immune system in AD patients to mount an effective antibody response against A␤ and, in particular, to induce immunological memory, may require a strong universal T-cell epitope such as T1 that does not cross-react with A␤ T-cell epitope(s).…”

Microglia as a Pharmacological Target in Infectious and Inflammatory Diseases of the Brain

“…However, the trial had to be prematurely stopped because of the development of severe meningoencephalitis in some patients related to vaccine-generated cytotoxic T cells. Recent analysis has demonstrated that prevaccine gene expression patterns indicative of proinflammatory pathways were associated with development of immunotherapy-related meningoencephalitis, whereas ex- pression of genes related to protein synthesis, protein trafficking, and DNA repair were strongly associated with a beneficial immunoglobulin G response to immunization (O'Toole et al, 2005).…”

Immunotherapy for Conformational Diseases

“…Recently, candidate biomarkers of risk for the development of meningoencephalitis have been identified in the patients enrolled in the phase IIa AN1792 trial [61]. In future trials, these potential markers as well as the haplotype of the individuals should be considered prior to enrollment.…”