Vaccine-induced Aβ-specific CD8+ T cells do not trigger autoimmune neuroinflammation in a murine model of Alzheimer's disease.

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)