Aβ-induced meningoencephalitis is IFN-γ-dependent and is associated with T cell-dependent clearance of Aβ in a mouse model of Alzheimer's disease

Abstract

Vaccination against amyloid ␤-peptide (A␤) has been shown to be successful in reducing A␤ burden and neurotoxicity in mouse models of Alzheimer's disease (AD). However, although A␤ immunization did not show T cell infiltrates in the brain of these mice, an A␤ vaccination trial resulted in meningoencephalitis in 6% of patients with AD. Here, we explore the characteristics and specificity of A␤-induced, T cell-mediated encephalitis in a mouse model of the disease. We demonstrate that a strong A␤-specific T cell response is critically dependent on the immunizing T cell epitope and that epitopes differ depending on MHC genetic background. The amounts and the ratio between the two forms and their deposition in the brain are affected by mutations in the APP and presenilin genes or the presence of the ApoE4 allele (3, 4). Immunolabeling of extracellular A␤ in the brain reveals neuritic and diffuse plaques. The former are colocalized with activated microglia and astrocytes as well as degenerating neurons, whereas the latter do not clearly associate with glial activation or neurotoxicity (5). Recent findings also demonstrate a role for A␤ synaptotoxicity independent of plaques, possibly mediated by soluble A␤ oligomers at intra-and extracellular compartments (6-9).Parenteral immunization of APP transgenic (Tg) mice with synthetic A␤ in adjuvant can markedly decrease the number and density of A␤ deposits in the brain, with concomitant improvement in neuritic dystrophy and gliosis (10, 11). Positive effects have also been found after repetitive mucosal (intranasal) administration of the A␤ peptide to Tg mice (12, 13). Passive transfer of A␤ antibodies has shown similar beneficial neuropathological effects (14-16); however, brain hemorrhage appears as a possible side effect of this approach if tested in mice with cerebral amyloid angiopathy (7).The finding that active vaccination with A␤ had profound A␤-lowering effects in an animal model of AD led to a clinical trial in which an A␤1-42 synthetic peptide was administered parenterally with adjuvant to patients with mild to moderate AD. Although a phase I safety study in a small number of patients did not reveal significant side effects, a subsequent phase II trial was discontinued shortly after its initiation, when Ϸ6% of the treated patients developed meningoencephalitis (17). Nonetheless, a cohort of patients with AD vaccinated with A␤ have shown promising results, demonstrating slower decline of cognitive functions over a 1-year period, which was evident also in patients who experienced transient encephalitis (18). Postmortem analysis of brain sections revealed decreased A␤ plaques in neocortex regions associated with activated microglia and T cell infiltrates in the CNS, as compared with unimmunized patients with AD (19).The meningoencephalitis observed after A␤ vaccination of patients with AD is postulated to be the result of activation of A␤-reactive T cells in the periphery and their migration to A␤ plaques in the brain. Understanding the factors that are required to ...

HLA-DR Alleles in Amyloid β-Peptide Autoimmunity: A Highly Immunogenic Role for the DRB1*1501 Allele

“…Clearance of A␤, achieved by A␤ vaccination, has been shown to prevent its deposition in the brain as well as the associated glial activation and cognitive deficits (7-14). In a clinical trial of AD patients, however, such treatment resulted in unexpected complications in the form of meningoencephalitis in ϳ6% of participants (15, 16), presumably caused by pathogenic activation of A␤-specific T cells in certain A␤-immunogenic individuals.The extent of A␤ T cell activation differs significantly among mouse strains bearing different MHC class II (MHC-II) haplotypes (17)(18)(19)(20). For example, SJL mice, which bear the H-2 s haplotype, were substantially more A␤-immunogenic than C57BL/6 mice, which bear the H-2 b haplotype (19).…”

Increased T Cell Recruitment to the CNS after Amyloid β1–42Immunization in Alzheimer's Mice Overproducing Transforming Growth Factor-β1

“…Adjuvant choice and genetic background have also been shown to influence T lymphocyte infiltration after A␤ 1-42 immunization (Seabrook et al, 2004). Increased levels of brain interferon-␥ can produce transient T lymphocyte infiltration after A␤ 1-42 immunization (Monsonego et al, 2006). Our data demonstrate that overall T lymphocyte number is increased chronically in the brain by local TGF-␤1 overexpression; similarly, local TGF-␤1 overexpression in the brains of AD patients may predispose them to T lymphocyte accumulation.…”

The genetics of the amyloidoses: interactions with immunity and inflammation

“…Unfortunately, perhaps predictably, about 5% of the immunized individuals developed severe inflammatory disease of the central nervous system. 100,101 The frequency of the severe adverse reaction was actually less than one might expect, considering that while the AD mice were being immunized with a human protein (less likely to be homologous to an endogenous functional murine molecule), the trial involved immunizing humans with a human protein and some autoreactivity was likely. Nonetheless pathologic examination of the brains of some of the individuals suggested reductions in plaques.…”