Differences in the immune response to long term A? vaccination in C57BL/6 and B6D2F1 mice

Seabrook, Timothy J.; Iglesias, Melitza; Bloom, Jerry; Spooner, E. T. C.; Lemere, Cynthia A.

doi:10.1016/j.vaccine.2004.03.061

Cited by 18 publications

(13 citation statements)

References 27 publications

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“…1). Of note, previously several groups, including us (Das et al, 2003;Petrushina et al, 2003;Seabrook et al, 2004;Kutzler et al, 2005), demonstrated that C57BL6 mice respond to fibrillar Aβ 42 poorly. The results generated here indicate that H-2 b immune haplotype does not respond to Aβ 28 peptide immunization, suggesting that these mice may not recognize a T-cell epitope within this peptide.…”

Section: Discussionmentioning

confidence: 89%

Aβ-Immunotherapy for Alzheimer's Disease Using Mannan–Amyloid-Beta Peptide Immunoconjugates

Ghochikyan

Petrushina

Lees³

et al. 2006

DNA and Cell Biology

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In Alzheimer's disease (AD) the accumulation of pathological forms of the beta-amyloid (Aβ) peptide are believed to be causal factors in the neurodegeneration that results in the loss of cognitive function in patients. Anti-Aβ antibodies have been shown to reduce Aβ levels in transgenic mouse models of AD and in AN-1792 clinical trial on AD patients; however, the clinical trial was halted when some patients developed meningoencephalitis. Theories on the cause of the adverse events include proinflammatory "primed patients," a Th1-inducing adjuvant, and Aβ autoreactive T cells. New immunotherapy approaches are being developed to eliminate these putative risk factors. Mannan, which is recognized by pattern recognition receptors of the innate immune system, can be utilized as a molecular adjuvant to promote a Th2-mediated immune response to conjugated B cell epitopes. The N-terminus of Aβ was conjugated to mannan, and used to immunize mice with low concentrations of immunoconjugate, without a conventional adjuvant. Mannan induced a significant and highly polarized toward Th2 phenotype anti-Aβ antibody response not only in BALB/c, but also in B6SJL F1 mice. New preclinical trials in AD mouse models may help to develop novel immunogen-adjuvant configurations with the potential to avoid the adverse immune response that occurred in the first clinical trial.

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Section: Discussionmentioning

confidence: 89%

Aβ-Immunotherapy for Alzheimer's Disease Using Mannan–Amyloid-Beta Peptide Immunoconjugates

Ghochikyan

Petrushina

Lees³

et al. 2006

DNA and Cell Biology

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“…The cerebral A␤ plaqueclearing effect of A␤ immunotherapy has been reported to be less effective when immunization is begun after plaque deposition is well underway. 13,19 In addition to active immunization, passive transfer by intraperitoneal injection of A␤ antibodies has been shown to reduce cerebral A␤ load if given before robust plaque deposition, 20 increase A␤ levels in blood, 21 and improve behavior in APP transgenic mice even in old mice in which cerebral A␤ loads were unchanged by immunization. [22][23][24][25] Several reports describe the occurrence of microhemorrhages after passive A␤ immunization in old APP transgenic mice with abundant vascular amyloid, although the presence of these microhemorrhages did not seem to negate the improvement in cognition.…”

Section: A␤ Immunotherapy In Mice and Ratsmentioning

confidence: 99%

“…The majority of A␤ antibodies generated by A␤ vaccination in mice, monkeys, and humans recognized B cell epitopes located within the amino-terminus of A␤ protein (within A␤1-16). 15,19,35,43,[51][52][53] In humans, T cells were shown to recognize an epitope in the A␤16-33 region, 54 whereas those in the mice recognized a region outside of A␤1-15 55 or within A␤6-28. 43 As noted, passive transfer with A␤ antibodies in mice resulted in lowered cerebral A␤ levels and improved cognition, implying that T-cell response was not required for the beneficial effects of A␤ vaccination.…”

Section: On the Road To Making A Safe And Effective Vaccine To Prevenmentioning

confidence: 99%

Amyloid-Beta Immunotherapy for the Prevention and Treatment of Alzheimer Disease: Lessons from Mice, Monkeys, and Humans

Lemere

Maier

Jiang

et al. 2006

Rejuvenation Research

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Alzheimer disease (AD), the most common form of dementia, is without an effective cure or preventive treatment. Recently, amyloid-beta protein (Abeta) has become a major therapeutic target. Many efforts are underway to either reduce the production of Abeta or enhance its clearance. In 1999, Schenk and colleagues first showed that active immunization with full-length Abeta lowered cerebral Abeta levels in transgenic mice. These findings have been confirmed and extended in various transgenic mouse models of AD using both active and passive Abeta immunization. Cognitive improvement also has been reported in association with active and passive Abeta vaccination in AD-like mouse models, even in the absence of significant reductions in cerebral Abeta loads. In 2004, the authors reported that active immunization with full-length Abeta in aged nonhuman primates, Caribbean vervets, reduced cerebral Abeta levels and gliosis. Proposed mechanisms of Abeta clearance by immunotherapy include disruption of Abeta aggregates, Abeta phagocytosis by microglia, neutralization of Abeta oligomers at the synapse, and increased efflux of Abeta from brain to blood. A phase IIa clinical trial was halted in 2002 because of the appearance of meningoencephalitis in approximately 6% of the AD patients. Although the exact cause of these adverse events is unknown, the immunogen, full-length Abeta1-42, may have been recognized as a self-antigen leading to an autoimmune response in some patients. Limited cognitive stabilization and apparent plaque clearance have been reported in subsets of patients who generated antibody titers. Currently, a passive immunization trial with a recombinant humanized monoclonal Abeta antibody is underway in humans. In the meantime, the authors are developing novel Abeta peptide immunogens for active immunization to target Abeta B cell epitope(s) and avoid Abeta-specific T-cell reactions in order to generate a safe and effective AD vaccine. The authors remain optimistic about the potential of such a vaccine for the prevention and treatment of AD.

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“…In APP/TGF-␤1 mice, the presence of antigen in the brain (A␤ in this case) may recruit antigen-specific T cells to that site. Adjuvant choice and genetic background have also been shown to influence T lymphocyte infiltration after A␤ 1-42 immunization (Seabrook et al, 2004). Increased levels of brain interferon-␥ can produce transient T lymphocyte infiltration after A␤ 1-42 immunization (Monsonego et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Increased T Cell Recruitment to the CNS after Amyloid β_1–42Immunization in Alzheimer's Mice Overproducing Transforming Growth Factor-β1

Buckwalter¹,

Coleman²,

Buttini³

et al. 2006

J. Neurosci.

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Differences in the immune response to long term A? vaccination in C57BL/6 and B6D2F1 mice

Cited by 18 publications

References 27 publications

Aβ-Immunotherapy for Alzheimer's Disease Using Mannan–Amyloid-Beta Peptide Immunoconjugates

Aβ-Immunotherapy for Alzheimer's Disease Using Mannan–Amyloid-Beta Peptide Immunoconjugates

Amyloid-Beta Immunotherapy for the Prevention and Treatment of Alzheimer Disease: Lessons from Mice, Monkeys, and Humans

Increased T Cell Recruitment to the CNS after Amyloid β_1–42Immunization in Alzheimer's Mice Overproducing Transforming Growth Factor-β1

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Differences in the immune response to long term A? vaccination in C57BL/6 and B6D2F1 mice

Cited by 18 publications

References 27 publications

Aβ-Immunotherapy for Alzheimer's Disease Using Mannan–Amyloid-Beta Peptide Immunoconjugates

Aβ-Immunotherapy for Alzheimer's Disease Using Mannan–Amyloid-Beta Peptide Immunoconjugates

Amyloid-Beta Immunotherapy for the Prevention and Treatment of Alzheimer Disease: Lessons from Mice, Monkeys, and Humans

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

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Product

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Increased T Cell Recruitment to the CNS after Amyloid β_1–42Immunization in Alzheimer's Mice Overproducing Transforming Growth Factor-β1