Abstract | BACKGROUND: Active 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. METHODS: Potential 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. RESULTS: We identified one nonamer peptide, Aβ33-41, which was naturally processed and presented in association with H-2-D(b) molecule on neurons and CD11b(+) microglia. Upon optimization of anchor residues for enhanced binding to H-2-D(b), 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. CONCLUSIONS: Altogether, these results suggest that Aβ-specific CD8(+) T cells are not major contributors to meningoencephalitis in response to Aβ vaccination.
|
Authors | Martine Bruley Rosset, Gabrielle Lui, Cira Dansokho, Thomas Chaigneau, Guillaume Dorothée |
Journal | Journal of neuroinflammation
(J Neuroinflammation)
Vol. 12
Pg. 95
(May 16 2015)
ISSN: 1742-2094 [Electronic] England |
PMID | 25982697
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
Chemical References |
- Amyloid beta-Peptides
- Amyloid beta-Protein Precursor
- Antibodies
- Epitopes, T-Lymphocyte
- HLA-A2 Antigen
- HLA-DR1 Antigen
- Histocompatibility Antigens Class I
- Peptide Fragments
- Presenilin-1
|
Topics |
- Alzheimer Disease
(complications, genetics, immunology, therapy)
- Amyloid beta-Peptides
(immunology, metabolism)
- Amyloid beta-Protein Precursor
(genetics)
- Animals
- Antibodies
(analysis)
- CD8-Positive T-Lymphocytes
(immunology, metabolism)
- Disease Models, Animal
- Encephalitis
(etiology, pathology)
- Epitopes, T-Lymphocyte
(immunology)
- HLA-A2 Antigen
(genetics, metabolism)
- HLA-DR1 Antigen
(genetics)
- Histocompatibility Antigens Class I
(genetics, metabolism)
- Humans
- Immunotherapy, Active
(adverse effects)
- Mice
- Mice, Inbred C57BL
- Mice, Transgenic
- Microglia
(immunology, metabolism)
- Mutation
(genetics)
- Peptide Fragments
(immunology)
- Presenilin-1
(genetics)
|