Abstract
BackgroundActive immunization against Aβ was reported to have a therapeutic effect in murine models of Alzheimer’s disease. Clinical Aβ vaccination trial AN1792 was interrupted due to the development in 6 % of the patients of meningoencephalitis likely involving pro-inflammatory CD4+ T cells. However, the potential implication of auto-aggressive anti-Aβ CD8+ T cells has been poorly investigated.MethodsPotential MHC-I-restricted Aβ-derived epitopes were first analyzed for their capacity to recruit functional CD8+ T cell responses in mouse models. Their impact on migration of CD8+ T cells into the brain parenchyma and potential induction of meningoencephalitis and/or neuronal damage was investigated upon vaccination in the APPPS1 mouse model of AD.ResultsWe identified one nonamer peptide, Aβ33-41, which was naturally processed and presented in association with H-2-Db molecule on neurons and CD11b+ microglia. Upon optimization of anchor residues for enhanced binding to H-2-Db, immunization with the modified Aβ33-41NP peptide elicited Aβ-specific IFNγ-secreting CD8+ T cells, which are cytotoxic towards Aβ-expressing targets. Whereas T cell infiltration in the brain of APPPS1 mice is dominated by CD3+CD8− T cells and increases with disease evolution between 4 and 7 months of age, a predominance of CD3+CD8+ over CD3+CD8− cells was observed in 6- to 7-month-old APPPS1 but not in WT animals, only after vaccination with Aβ33-41NP. The number of CD11b+ mononuclear phagocytes, which significantly increases with age in the brain of APPPS1 mice, was reduced following immunization with Aβ33-41NP. Despite peripheral activation of Aβ-specific CD8+ cytotoxic effectors and enhanced infiltration of CD8+ T cells in the brain of Aβ33-41NP-immunized APPPS1 mice, no clinical signs of severe autoimmune neuroinflammation were observed.ConclusionsAltogether, these results suggest that Aβ-specific CD8+ T cells are not major contributors to meningoencephalitis in response to Aβ vaccination.
Highlights
Active immunization against amyloid-β peptide (Aβ) was reported to have a therapeutic effect in murine models of Alzheimer’s disease
Whereas T cell infiltration in the brain of APPPS1 mice is dominated by CD3+CD8− T cells and increases with disease evolution between 4 and 7 months of age, a predominance of CD3+CD8+ over CD3+CD8− cells was observed in 6- to 7-month-old APPPS1 but not in wild type (WT) animals, only after vaccination with Aβ33-41NP
Failure of these trials underlined the need for readdressing the therapeutic capability of antibodies alone, and the role of T cells in the therapeutic effect and/or meningoencephalitis observed in initial immunization studies based on vaccination with full-length Aβ
Summary
Active immunization against Aβ was reported to have a therapeutic effect in murine models of Alzheimer’s disease. Second-generation immunotherapy trials that rely exclusively on Aβ-specific antibodies were initiated, based either on the intravenous infusion of humanized anti-Aβ monoclonal antibodies (mAbs) or vaccination strategies using the N-terminal portion of Aβ to elicit antibodies without inducing Aβ-specific T cell responses Among these strategies, trials with bapineuzumab [9, 10] and solanezumab [11] were the most advanced, but results of phase 3 studies released in summer 2012 indicated that both antibodies were inefficient at improving cognitive performance in AD patients. Enhanced expression of IFNγ in the brain of APP-Tg mice promotes T cell infiltration targeted primarily to the sites of Aβ deposition and was associated with both clearance of Aβ and transient encephalitis upon immunization with Aβ10-24, in the absence of antibodies to Aβ [18] These reports suggest that the magnitude of Aβ-specific CD4+ T cell responses critically depends on the nature of Aβ-derived T cell epitopes, which significantly vary with MHC genotype. Inappropriate boosting of endogenous naturally occurring Aβ-specific CD4+ T cell responses, e.g. through vaccination in the presence of a Th1 adjuvant, may likely be involved in the development of meningoencephalitis in selected AN1792 patients displaying given MHC haplotypes
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