Top

Journal of Neuroinflammation

Published in:

Open Access 01-12-2015 | Research

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

Authors: Martine Bruley Rosset, Gabrielle Lui, Cira Dansokho, Thomas Chaigneau, Guillaume Dorothée

Published in: Journal of Neuroinflammation | Issue 1/2015

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.

Janus C, Pearson J, McLaurin J, Mathews PM, Jiang Y, Schmidt SD, et al. A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer’s disease. Nature. 2000;408:979–82.CrossRefPubMed

Morgan D, Diamond DM, Gottschall PE, Ugen KE, Dickey C, Hardy J, et al. A beta peptide vaccination prevents memory loss in an animal model of Alzheimer’s disease. Nature. 2000;408:982–5.CrossRefPubMed

Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H, Guido T, et al. Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature. 1999;400:173–7.CrossRefPubMed

Bard F, Cannon C, Barbour R, Burke RL, Games D, Grajeda H, et al. Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat Med. 2000;6:916–9.PubMed

DeMattos RB, Bales KR, Cummins DJ, Dodart JC, Paul SM, Holtzman DM. Peripheral anti-A beta antibody alters CNS and plasma A beta clearance and decreases brain A beta burden in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci U S A. 2001;98:8850–5.PubMedCentralPubMed

Gilman S, Koller M, Black RS, Jenkins L, Griffith SG, Fox NC, et al. Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology. 2005;64:1553–62.CrossRefPubMed

Ferrer I, Boada Rovira M, Sanchez Guerra ML, Rey MJ, Costa-Jussa F. Neuropathology and pathogenesis of encephalitis following amyloid-beta immunization in Alzheimer’s disease. Brain Pathol. 2004;14:11–20.PubMed

Nicoll JA, Wilkinson D, Holmes C, Steart P, Markham H, Weller RO. Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report. Nat Med. 2003;9:448–52.PubMed

Rinne JO, Brooks DJ, Rossor MN, Fox NC, Bullock R, Klunk WE, et al. 11C-PiB PET assessment of change in fibrillar amyloid-beta load in patients with Alzheimer’s disease treated with bapineuzumab: a phase 2, double-blind, placebo-controlled, ascending-dose study. Lancet Neurol. 2010;9:363–72.PubMed

10.

Salloway S, Sperling R, Gilman S, Fox NC, Blennow K, Raskind M, et al. A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease. Neurology. 2009;73:2061–70.CrossRefPubMedCentralPubMed

11.

Farlow M, Arnold SE, van Dyck CH, Aisen PS, Snider BJ, Porsteinsson AP, et al. Safety and biomarker effects of solanezumab in patients with Alzheimer’s disease. Alzheimers Dement. 2012;8:261–71.PubMed

12.

Monsonego A, Zota V, Karni A, Krieger JI, Bar-Or A, Bitan G, et al. Increased T cell reactivity to amyloid beta protein in older humans and patients with Alzheimer disease. J Clin Invest. 2003;112:415–22.PubMedCentralPubMed

13.

Zota V, Nemirovsky A, Baron R, Fisher Y, Selkoe DJ, Altmann DM, et al. HLA-DR alleles in amyloid beta-peptide autoimmunity: a highly immunogenic role for the DRB1*1501 allele. J Immunol. 2009;183:3522–30.PubMed

14.

Das P, Chapoval S, Howard V, David CS, Golde TE. Immune responses against Abeta1-42 in HLA class II transgenic mice: implications for Abeta1-42 immune-mediated therapies. Neurobiol Aging. 2003;24:969–76.PubMed

15.

Kutzler MA, Cao C, Bai Y, Dong H, Choe PY, Saulino V, et al. Mapping of immune responses following wild-type and mutant ABeta42 plasmid or peptide vaccination in different mouse haplotypes and HLA class II transgenic mice. Vaccine. 2006;24:4630–9.CrossRefPubMed

16.

Seabrook TJ, Iglesias M, Bloom JK, Spooner ET, Lemere CA. Differences in the immune response to long term Abeta vaccination in C57BL/6 and B6D2F1 mice. Vaccine. 2004;22:4075–83.CrossRefPubMed

17.

Toly-Ndour C, Lui G, Nunes MM, Bruley-Rosset M, Aucouturier P, Dorothee G. MHC-independent genetic factors control the magnitude of CD4+ T cell responses to amyloid-beta peptide in mice through regulatory T cell-mediated inhibition. J Immunol. 2011;187:4492–500.PubMed

18.

Monsonego A, Imitola J, Petrovic S, Zota V, Nemirovsky A, Baron R, et al. Abeta-induced meningoencephalitis is IFN-gamma-dependent and is associated with T cell-dependent clearance of Abeta in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci U S A. 2006;103:5048–53.PubMedCentralPubMed

19.

Neumann H, Medana IM, Bauer J, Lassmann H. Cytotoxic T lymphocytes in autoimmune and degenerative CNS diseases. Trends Neurosci. 2002;25:313–9.PubMed

20.

Pascolo S, Bervas N, Ure JM, Smith AG, Lemonnier FA, Perarnau B. HLA-A2.1-restricted education and cytolytic activity of CD8(+) T lymphocytes from beta2 microglobulin (beta2m) HLA-A2.1 monochain transgenic H-2Db beta2m double knockout mice. J Exp Med. 1997;185:2043–51.PubMedCentralPubMed

21.

Pajot A, Michel ML, Fazilleau N, Pancre V, Auriault C, Ojcius DM, et al. A mouse model of human adaptive immune functions: HLA-A2.1-/HLA-DR1-transgenic H-2 class I-/class II-knockout mice. Eur J Immunol. 2004;34:3060–9.PubMed

22.

Radde R, Bolmont T, Kaeser SA, Coomaraswamy J, Lindau D, Stoltze L, et al. Abeta42-driven cerebral amyloidosis in transgenic mice reveals early and robust pathology. EMBO Rep. 2006;7:940–6.PubMedCentralPubMed

23.

Gregoire S, Logre C, Metharom P, Loing E, Chomilier J, Rosset MB, et al. Identification of two immunogenic domains of the prion protein—PrP—which activate class II-restricted T cells and elicit antibody responses against the native molecule. J Leukoc Biol. 2004;76:125–34.PubMed

24.

Tourdot S, Oukka M, Manuguerra JC, Magafa V, Vergnon I, Riche N, et al. Chimeric peptides: a new approach to enhancing the immunogenicity of peptides with low MHC class I affinity: application in antiviral vaccination. J Immunol. 1997;159:2391–8.PubMed

25.

Buc-Caron MH, Launay JM, Lamblin D, Kellermann O. Serotonin uptake, storage, and synthesis in an immortalized committed cell line derived from mouse teratocarcinoma. Proc Natl Acad Sci U S A. 1990;87:1922–6.PubMedCentralPubMed

26.

Mouillet-Richard S, Mutel V, Loric S, Tournois C, Launay JM, Kellermann O. Regulation by neurotransmitter receptors of serotonergic or catecholaminergic neuronal cell differentiation. J Biol Chem. 2000;275:9186–92.PubMed

27.

Agadjanyan MG, Ghochikyan A, Petrushina I, Vasilevko V, Movsesyan N, Mkrtichyan M, et al. Prototype Alzheimer’s disease vaccine using the immunodominant B cell epitope from beta-amyloid and promiscuous T cell epitope pan HLA DR-binding peptide. J Immunol. 2005;174:1580–6.PubMed

28.

Gross DA, Graff-Dubois S, Opolon P, Cornet S, Alves P, Bennaceur-Griscelli A, et al. High vaccination efficiency of low-affinity epitopes in antitumor immunotherapy. J Clin Invest. 2004;113:425–33.PubMedCentralPubMed

29.

Sacquin A, Chaigneau T, Defaweux V, Adam M, Schneider B, Bruley Rosset M, et al. Prolongation of prion disease-associated symptomatic phase relates to CD3+ T cell recruitment into the CNS in murine scrapie-infected mice. Brain Behav Immun. 2012;26:919–30.PubMed

30.

Monsonego A, Maron R, Zota V, Selkoe DJ, Weiner HL. Immune hyporesponsiveness to amyloid beta-peptide in amyloid precursor protein transgenic mice: implications for the pathogenesis and treatment of Alzheimer’s disease. Proc Natl Acad Sci U S A. 2001;98:10273–8.PubMedCentralPubMed

31.

Westermann J, Pabst R. How organ-specific is the migration of ‘naive’ and ‘memory’ T cells? Immunol Today. 1996;17:278–82.PubMed

32.

Togo T, Akiyama H, Iseki E, Kondo H, Ikeda K, Kato M, et al. Occurrence of T cells in the brain of Alzheimer’s disease and other neurological diseases. J Neuroimmunol. 2002;124:83–92.PubMed

33.

Galea I, Bernardes-Silva M, Forse PA, van Rooijen N, Liblau RS, Perry VH. An antigen-specific pathway for CD8 T cells across the blood–brain barrier. J Exp Med. 2007;204:2023–30.PubMedCentralPubMed

34.

Joly E, Oldstone MB. Neuronal cells are deficient in loading peptides onto MHC class I molecules. Neuron. 1992;8:1185–90.CrossRefPubMed

35.

Keane RW, Tallent MW, Podack ER. Resistance and susceptibility of neural cells to lysis by cytotoxic lymphocytes and by cytolytic granules. Transplantation. 1992;54:520–6.PubMed

36.

Galea I, Bechmann I, Perry VH. What is immune privilege (not)? Trends Immunol. 2007;28:12–8.PubMed

37.

Ransohoff RM, Engelhardt B. The anatomical and cellular basis of immune surveillance in the central nervous system. Nat Rev Immunol. 2012;12:623–35.PubMed

38.

Monsonego A, Nemirovsky A, Harpaz I. CD4 T cells in immunity and immunotherapy of Alzheimer’s disease. Immunology. 2013;139:438–46.CrossRefPubMedCentralPubMed

39.

Perry VH, Holmes C. Microglial priming in neurodegenerative disease. Nat Rev Neurol. 2014;10:217–24.PubMed

40.

Perry VH, Nicoll JA, Holmes C. Microglia in neurodegenerative disease. Nat Rev Neurol. 2010;6:193–201.PubMed

Title: Vaccine-induced Aβ-specific CD8+ T cells do not trigger autoimmune neuroinflammation in a murine model of Alzheimer’s disease
Authors: Martine Bruley Rosset
Gabrielle Lui
Cira Dansokho
Thomas Chaigneau
Guillaume Dorothée
Publication date: 01-12-2015
Publisher: BioMed Central
Published in: Journal of Neuroinflammation / Issue 1/2015
Electronic ISSN: 1742-2094
DOI: https://doi.org/10.1186/s12974-015-0317-5

At a glance: The STEP trials

Springer Medicine

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

Abstract

Background

Methods

Results

Conclusions

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2015

Cytosolic phospholipase A2 plays a crucial role in ROS/NO signaling during microglial activation through the lipoxygenase pathway

1,25-Dihydroxyvitamin D3 attenuates endotoxin-induced production of inflammatory mediators by inhibiting MAPK activation in primary cortical neuron-glia cultures

Lipopolysaccharide binding protein, interleukin-10, interleukin-6 and C-reactive protein blood levels in acute ischemic stroke patients with post-stroke infection

Early inflammatory mediator gene expression in two models of traumatic brain injury: ex vivo cortical slice in mice and in vivo cortical impact in piglets

Vitamin D deficiency decreases survival of bacterial meningoencephalitis in mice

Sphingosine 1-phosphate enhances the excitability of rat sensory neurons through activation of sphingosine 1-phosphate receptors 1 and/or 3