Brain, Vol. 126, No. 2, 285-291,
February 2003
© 2003 Guarantors of Brain
doi: 10.1093/brain/awg031
Vaccination with amyloid-ß peptide induces autoimmune encephalomyelitis in C57/BL6 mice
1 Neuroimmunology Unit and 2 Department of Pathology, San Raffaele Scientific Institute, 3 Department of Neurology, University Vita-Salute, San Raffaele Hospital, Milan and 4 Department of Neurosciences, Ophthalmology and Genetics, University of Genoa, Genoa, Italy
Correspondence to: Dr Gianvito Martino, Neuroimmunology Unit – DIBIT, Department of Neuroscience, San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan, Italy E-mail: martino.gianvito{at}hsr.it
Received July 11, 2002. Revised August 14, 2002. Accepted August 23, 2002.
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Summary |
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Recent experimental evidence shows that vaccination with amyloid-ß peptide (Aß) of transgenic mouse models of Alzheimer’s disease protects from the pathological accumulation of amyloid within the CNS. Phase I/II clinical trials of Aß vaccination in mild to moderate Alzheimer’s disease have been undertaken. Un expectedly, one of these trials has been suspended because 15 patients showed clinical signs consistent with CNS inflammation. Here, we show that C57BL/6 mice immunized with Aß1–42 peptide develop an inflammatory disease of the CNS characterized by the presence both in the brain and spinal cord of perivenular inflammatory foci containing macrophages, T and B cells, and immunoglobulins. The experimental disease was observed only when pertussis toxin, an agent known to favour autoimmune processes, was co-administered. The immune-mediated CNS reaction was associated to Aß-induced CD4+ cells showing a Th1-type cytokine expression profile and to elevated levels of circulating anti-Aß immunoglobulins. Our results indicate that vaccination with Aß could determine, under certain circumstances, an aberrant autoimmune-type reaction to Aß resulting in a perivenular inflammatory encephalomyelitis.
Keywords: amyloid-ß peptide; Alzheimer’s disease; encephalomyelitis; vaccination
Abbreviations: Aß peptide= amyloid-ß peptide; APP = amyloid precursor protein; EAE = experimental autoimmune encephalomyelitis; IFN
= interferon gamma; IgG = immunoglobin G; IL-4 = interleukin-4; MOG = myelin oligodendrocyte glycoprotein; p.i. = post-immunization; PT = pertussis toxin
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Introduction |
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The abnormal processing and extracellular deposition of amyloid-ß (Aß) peptide, a proteolytic derivative of the amyloid precursor protein (APP), leading to the accumulation of fibrils formed from the Aß 40–42 amino acid long peptides into amyloid plaques, is a defining characteristic of Alzheimer’s disease (for review, see Steiner et al., 1999
). Recent evidence suggests that vaccination of transgenic mouse models of Alzheimer’s disease with Aß causes a marked reduction in brain amyloid burden (Schenk et al., 1999; Janus et al., 2000) and protects these mice from learning and age-related memory deficits (Janus et al., 2000; Morgan et al., 2000). However, the immunological mechanism underlying the protective effect of Aß-vaccination in Alzheimer’s disease is still not fully determined—apart from the observation that anti-Aß antibodies trigger microglial cells to clear amyloid plaques through Fc receptor-mediated phagocytosis (Bard et al., 2000). Based on these results, phase I/II studies with Aß have been initiated in Alzheimer’s disease patients with mild to moderate disease (Thatte et al., 2001). Here we show that vaccination with Aß could, in certain circumstances, determine an aberrant autoimmune Th1-type reaction to Aß within the CNS, resulting in a perivenular inflammatory encephalomyelitis where macrophages might represent the final effector cells.
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Methods |
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Immunization procedures
Female C57BL/6 mice, 6–8 weeks old, were immunized with incomplete Freund’s adjuvant (Sigma, St Louis, MO, USA) supplemented with 4 mg/ml mycobacterium tuberculosis (strain H37Ra; Difco, Detroit, MI, USA) [complete Freund’s adjuvant (CFA)], and 100 µg of Aß1–42 peptide (American Peptide Company, Sunnyvale, CA, USA). Immunization with Aß1–42 peptide was followed or not by intravenous administration of 500 ng of pertussis toxin (PT) (Sigma) the same day and 48 h later. Mice immunized with 150 µg of Aß42–1 (BioSource International, Camarillo, CA, USA), 200 µg of myelin oligodendrocyte glycoprotein (MOG) 35–55 peptide (Multiple Peptide Systems, San Diego, CA, USA) or CFA alone, served as controls. Clinical score was recorded daily as follows: 0 = healthy; 1 = transient symptoms suggestive of tail paresis and/or ataxic gait lasting <3 days; 2 = persistent symptoms indicating tail paralysis and gait disturbances lasting >3 days; 3 = paresis of hind-limbs, 4 = paralysis of hind-limbs and/or paresis of forelimbs, 5 = tetra-paralysis, 6 = moribund or death.
All procedures involving animals were performed according to the guidelines of The Animal Ethical Committee of our Institute (IACUC).
Immunological assays
Draining lymph nodes were removed and 4 x 105 lymph node cells per well were cultured in 96-well culture plates (Costar, Cambridge, MA, USA) in synthetic HL-1 medium (Ventrex Laboratories, Portland, ME, USA) supplemented with 2 mM L-glutamine and 50 mg/ml gentamicin (Sigma) and serial concentrations (0.3-10 µM) of Aß1–42 or MOG35–55. For the T cell proliferation assay, cultures were incubated for 3 days and subsequently pulsed 8 h before harvesting with 1 µCi [3H]thymidine (40 Ci/nmol, The Radiochemical Centre, Amersham, UK). Incorporation of [3H]thymidine was measured by liquid scintillation spectrometry.
Intracytoplasmatic staining for interferon gamma (IFN) and interleukin-4 (IL-4) production was performed on lymph node cells cultured with 10 µM of Aß1–42 or MOG35–55. After culture, living cells separated on a gradient (Lymphoprep, Axis-Shield, Oslo, Norway) were re-stimulated with 1 µg phorbol myristate acetate (PMA, Sigma) and 50 ng ionomycin (Sigma) for 4 h at 37°C, in the presence of 10 µg/ml brefeldin A (Novartis, Basel, Switzerland) to prevent egress of newly synthesized proteins from the endoplasmic reticulum. After fixing with 4% paraformaldehyde for 20 min at room temperature, cells were stained for CD4/CD8 and IFN/IL-4 as previously described (Openshaw et al., 1995).
Anti-Aß1–42 immunoglobin G (IgG), IgG1 and IgG2a were detected using biotinylated goat anti-mouse IgG (Vector Laboratories, Burlingame, CA, USA), IgG1 and IgG2a (Southern Biotechnology Associates, Birmingham, AL, USA) antibodies using a previously described home-made enzyme-linked immunosorbent assay (ELISA) (Moiola et al., 1998).
Neuropathological features in experimental autoimmune encephalomyelitis (EAE) mice
At the time of sacrifice, mice were perfused with 4% paraformaldehyde and the brain, spinal cord, spleen, liver, lungs, heart, gastrointestinal tract, kidneys, muscles and skin were removed and embedded in paraffin. Four µm microtome sections were cut from all organs and stained with haematoxilin and eosin or processed for immunohystochemistry. Luxol Fast Blue staining was performed on brain and spinal cord tissue sections. The following antibodies were used: rat anti-mouse CD3 (pan-T cell marker; Serotec Ltd, Oxford, UK), rat anti-CD45R antibody (B cell marker; B220, Pharmingen, San Diego, CA, USA) and tetramethyl rhodamine isothiocyanate (TRITC) conjugated goat anti-mouse IgG (Molecular Probes, Eugene, OR, USA). Macrophages were stained with biotin-conjugated BS-I isolectin B4 (Sigma). Appropriate secondary antibodies were used when needed.
CNS damage was scored as follows: 10 = traces of leptomeningeal or subpial inflammation; 20 = mild leptomeningeal or subpial inflammation with scarce or no perivascular inflammatory cell aggregates; 30 = moderate leptomeningeal or subpial inflammation with presence of perivascular inflammatory cell aggregates; 40 = leptomeningeal and subpial inflammation with presence of inflammatory cell aggregates in the perivascular space and in the CNS parenchyma.
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Results |
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We immunized C57BL/6 mice with 100 µg of Aß1–42 (hereafter referred as Aß), adopting the same schedule and dosing as described previously for the Aß vaccination protocol (Schenk et al., 1999
). To boost the T cell immune response against Aß, we also studied, in parallel, an additional group of five C57BL/6 mice immunized with 100 µg of Aß and injected intravenously twice with 500 ng of PT (on the day of the immunization and 2 days later). PT was used because of its ability to increase predisposition to autoimmune diseases, possibly inhibiting tolerance mechanisms that normally operate within secondary lymphoid tissues (Cyster et al., 1995). As expected, none of the mice immunized with Aß alone showed any abnormality up to 60 days after immunization. Conversely, all five mice immunized with Aß and PT developed symptoms and signs evocative of a neurological disorder affecting the CNS between 13 and 20 days post-immunization (p.i.) (Table 1). Symptoms and signs lasted for up to 75 days, with a caudo-cranial progression and a chronic course, making them indistinguishable from those observed in chronic forms of mouse EAE.
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To confirm our preliminary data and to exclude a ‘non-specific’ CNS effect, 13 additional mice were immunized with 100 µg Aß and 1 µg PT, and five mice were immunized with 100 µg Aß but not PT. Three mice immunized with 150 µg of the reverse Aß42–1 peptide and 1 µg of PT, and seven mice immunized with CFA and 1 µg of PT served as additional controls. The results are summarized in Table 1. A total of 89% (16 out of 18) of the mice immunized with Aß and PT developed a CNS disease, while only 10% (1 out of 10) of the mice immunized with Aß alone and 10% (1 out of 10) of the control mice showed minimal clinical symptoms (see Table 1). All ‘positive’ control C57BL/6 mice immunized with 200 µg of MOG35–55 and 1 µg of PT developed the classical chronic-progressive form of EAE (Furlan et al., 2001
).
In all mice treated with Aß and PT, we found inflammatory aggregates of macrophages and T cells, surrounding small venules within the leptomeningeal space (Fig. 1A) and the brain and spinal cord parenchyma (Fig. 1B and C). Focal inflammatory aggregates were also seen inside the brain and spinal cord parenchyma (Fig. 1F–J). Limited areas of demyelination and myelin debris-containing macrophages were seen around some aggregates (Fig. 1D and E). However, demyelination was not widespread within the CNS compared with EAE mice (Furlan et al., 2001) and was confined to the subpial and the perivascular space. Inflammatory CNS infiltrates appeared 20 days p.i. and were still present at 75 days p.i. These results support a major role for T cells and macrophages in the pathogenesis of this encephalomyelitis.
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We then analysed mice immunized with CFA and PT only. We found macrophages, but not T cells, infiltrating the leptomeningeal space and, occasionally, the perivascular space (Table 1). This latter finding, possibly due to PT injection, may explain the transient mild neurological signs lasting <3 days that we have rarely seen in control mice. In six out of 14 mice co-treated with Aß and PT and sacrificed between 60 and 75 days p.i., but not in control mice or MOG35–55 immunized mice, we observed spotty necrotic foci in the spleen and diffuse perivenular neutrophilic aggregates in the connective tissues of the gastrointestinal tract (data not shown).
Since these results were suggestive of a T cell-mediated inflammatory autoimmune disease of the CNS, we analysed the T cell response against Aß. In draining lymph nodes of mice treated with Aß and PT, we found a clear dose-dependent T-cell response against Aß (Fig. 2A). This response was of a Th1-type as indicated by the significant increase of the percentage of Aß-specific CD4+ T cells producing IFN (Fig. 2B). CD4+ cells producing IL-4 and CD8+ cells producing either IL-4 or IFN were virtually absent (Fig. 2B and C).
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Next, we analysed the B cell response against Aß. As expected, anti-Aß IgG antibodies were found in serum samples of mice treated with Aß irrespective of PT administration (Fig. 3A). Interestingly, anti-Aß IgG appeared earlier in mice treated with Aß alone (10 days p.i.) compared with mice co-treated with Aß and PT (30 days p.i.) and persisted, in both groups, up to 75 days p.i. We then measured anti-Aß IgG subclasses. We found a predominant IgG2a (Fig. 3B) versus IgG1 (Fig. 3C) anti-Aß response. Anti-Aß IgG1 was at a very low level and was detectable only 30 days p.i. (Fig. 3C). Conversely, IgG2a appeared at day 10 p.i. and increased up to 75 days p.i. (Fig. 3B).
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Since Th1-derived IgG2a antibody are complement fixing and participate in macrophage activation and opsonization, we analysed CNS tissue samples from mice co-treated with Aß and PT to analyse B cells and IgG deposition in areas of chronic inflammation. We found a consistent number of B cells infiltrating the perivenular spaces of the CNS (Fig. 3D and E) as well as deposits of IgG in the same areas (Fig. 3F).
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Discussion |
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TopSummaryIntroductionMethodsResultsDiscussionReferences |
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Our results indicate that vaccination with Aß may trigger an aberrant autoimmune reaction against Aß leading to a perivenular inflammatory encephalomyelitis. This reaction is associated with Th1-like Aß-specific T cells, B cells producing complement-fixing anti-Aß antibodies and macrophages, which possibly represent the final effector cells.
The key role of PT in the induction of this CNS-confined autoimmune reaction is clearly indicated by the lack of any abnormal sign or symptom in the CNS of C57BL/6 mice that did not receive PT. The use of PT explains the discrepancy between our results and those indicating that Aß vaccination (without PT) induced a protective immune response against Aß in transgenic mouse models of Alzheimer’s disease (Schenk et al., 1999; Janus et al., 2000; Morgan et al., 2000). However, the occurrence of a CNS-confined autoimmune reaction against a ubiquitous protein, such as Aß (Kang et al., 1987) only when PT is co-administered, remains a challenging phenomenon. Some likely explanations can be put forward. PT favours CNS trafficking of blood-borne mononuclear cells by increasing the vascular permeability of cerebral endothelium (Linthicum and Frelinger, 1982; Linthicum et al., 1982). This facilitates CNS-confined (auto)immune reactions, as indicated by the spontaneous occurrence of EAE in T cell receptor transgenic mice for myelin basic protein immunized with PT (Goverman et al., 1993, 1997). Furthermore, CNS vessels are a preferential location for the pathological accumulation of amyloid, possibly owing to a site-specific abnormal processing of APP (e.g. cerebral amyloid angiopathies) (Suzuki et al., 1994; Thomas et al., 1996). This might favour the site-restricted deposit of a normally sequestered antigen, a process which can, in turn, trigger a T cell-mediated (auto)immune reaction.
In mice vaccinated with Aß and PT, we also measured increased levels of circulating complement-fixing anti-Aß IgG2a. This finding, along with the presence of B cells and IgGs within demyelinating areas of vaccinated mice, suggest these Th1-type antibodies might contribute to the disease process. This is only in apparent contrast with the protective role of anti-Aß antibodies that, in transgenic mouse models of Alzheimer’s disease, trigger microglial cells to clear amyloid plaques via complement components (Bard et al., 2000; Brazil et al., 2000; Webster et al., 2001). Complement-fixing antibodies may, in fact, be both protective and pathogenic, depending on the circumstances, owing to their opsonising ability (Abbas et al., 1996).
The data reported here support the notion that the use of Aß vaccination may lead to an aberrant autoimmune reaction against Aß provoking CNS inflammation. This experimental evidence may explain the unexpected appearance of clinical signs consistent with CNS inflammation occurring in 15 patients with Alzheimer’s disease undergoing the Aß vaccination trial (i.e. AN-1792 trial). Consistent with our data, this adverse event, leading to the definitive suspension of the AN-1792 trial (Birmingham and Frantz, 2002), can be bona fide attributed to an (auto)immune mediated process confined to the CNS and triggered by the Aß vaccination protocol since the spinal taps from the 15 patients showed elevated protein and lymphocyte levels but absence of bacteria or viruses (http://www.elan.com/NewsRoom/).
In conclusion, our work reports a novel observation clearly indicating that a CNS-confined autoimmune reaction against a self-protein such as APP/Aß can be induced in mice by a vaccination protocol. Thus, a therapeutic approach based on Aß vaccination can be also detrimental and not exclusively protective, as previously suggested in transgenic mouse models of Alzheimer’s disease (Schenk et al., 1999; Janus et al., 2000; Morgan et al., 2000). Our data challenge the hypothetical idea to use Aß vaccination as a treatment option for Alzheimer’s disease.
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Acknowledgements |
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We wish to thank Luciano Adorini for the critical review of the manuscript. This work was supported by the Italian Ministry of Health (Progetto Strategico ‘Alzheimer’). Antonio Uccelli is co-affiliated to the Centre for the Study of Cell to Cell Interaction of the University of Genoa.
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