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).…”

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).…”

Increased T Cell Recruitment to the CNS after Amyloid β1–42Immunization in Alzheimer's Mice Overproducing Transforming Growth Factor-β1

“…New techniques that modulate the immune response to A␤ are being developed (Kim et al, 2005;Maier et al, 2006). Peripheral blood from patients in the AN1792 immunization trial demonstrated increases in mul- tiple pro-inflammatory genes in those who would go on to develop symptoms after immunization, implying that peripheral immune status influenced the possibility of development of meningoencephalitis after treatment with AN1792 (O'Toole et al, 2005). Our study demonstrates that increases in brain TGF-␤1 can influence the number of T cells in the brain and provides a starting point for understanding how to design therapies that produce a targeted, safe, specific immune response to A␤ in AD patients.…”

Immunization With β-Amyloid(1-42) Protein for Alzheimer Disease: Genomics Predicts the Response

“…3,4 Because of the highly positive amyloid burden reduction in A␤ in Alzheimer disease transgenic mice, 5-8 a phase 2, double-blind, placebo-controlled, multicenter study was conducted to evaluate safety, tolerability, and pilot efficacy of AN1792 (A␤ 1-42 ) administered with QS-21 adjuvant in 372 patients with mild to moderate Alzheimer disease. 9 Meningoencephalitis associated with AN1792 immunization developed in 18 of 300 immunized patients and this study had to be stopped. When the study was stopped, 24 patients had received 3 immunizations and 274 patients had received 2 immunizations.…”

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).…”

Increased T Cell Recruitment to the CNS after Amyloid β1–42Immunization in Alzheimer's Mice Overproducing Transforming Growth Factor-β1

“…New techniques that modulate the immune response to A␤ are being developed (Kim et al, 2005;Maier et al, 2006). Peripheral blood from patients in the AN1792 immunization trial demonstrated increases in mul- tiple pro-inflammatory genes in those who would go on to develop symptoms after immunization, implying that peripheral immune status influenced the possibility of development of meningoencephalitis after treatment with AN1792 (O'Toole et al, 2005). Our study demonstrates that increases in brain TGF-␤1 can influence the number of T cells in the brain and provides a starting point for understanding how to design therapies that produce a targeted, safe, specific immune response to A␤ in AD patients.…”

Immunization With β-Amyloid(1-42) Protein for Alzheimer Disease: Genomics Predicts the Response

“…3,4 Because of the highly positive amyloid burden reduction in A␤ in Alzheimer disease transgenic mice, 5-8 a phase 2, double-blind, placebo-controlled, multicenter study was conducted to evaluate safety, tolerability, and pilot efficacy of AN1792 (A␤ 1-42 ) administered with QS-21 adjuvant in 372 patients with mild to moderate Alzheimer disease. 9 Meningoencephalitis associated with AN1792 immunization developed in 18 of 300 immunized patients and this study had to be stopped. When the study was stopped, 24 patients had received 3 immunizations and 274 patients had received 2 immunizations.…”

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).…”

Increased T Cell Recruitment to the CNS after Amyloid β1–42Immunization in Alzheimer's Mice Overproducing Transforming Growth Factor-β1

“…New techniques that modulate the immune response to A␤ are being developed (Kim et al, 2005;Maier et al, 2006). Peripheral blood from patients in the AN1792 immunization trial demonstrated increases in mul- tiple pro-inflammatory genes in those who would go on to develop symptoms after immunization, implying that peripheral immune status influenced the possibility of development of meningoencephalitis after treatment with AN1792 (O'Toole et al, 2005). Our study demonstrates that increases in brain TGF-␤1 can influence the number of T cells in the brain and provides a starting point for understanding how to design therapies that produce a targeted, safe, specific immune response to A␤ in AD patients.…”

Immunization With β-Amyloid(1-42) Protein for Alzheimer Disease: Genomics Predicts the Response

“…3,4 Because of the highly positive amyloid burden reduction in A␤ in Alzheimer disease transgenic mice, 5-8 a phase 2, double-blind, placebo-controlled, multicenter study was conducted to evaluate safety, tolerability, and pilot efficacy of AN1792 (A␤ 1-42 ) administered with QS-21 adjuvant in 372 patients with mild to moderate Alzheimer disease. 9 Meningoencephalitis associated with AN1792 immunization developed in 18 of 300 immunized patients and this study had to be stopped. When the study was stopped, 24 patients had received 3 immunizations and 274 patients had received 2 immunizations.…”