CD4 T cells in immunity and immunotherapy of Alzheimer's disease

Abstract

SummaryAlzheimer's disease (AD) is the most common form of dementia, with prevalence progressively increasing with aging. Pathological hallmarks of the disease include accumulation of amyloid b-protein (Ab) peptides and neurofibrillary tangles in the brain associated with glial activation and synaptotoxicity. In addition, AD involves peripheral and brain endogenous inflammatory processes that appear to enhance disease progression. More than a decade ago a new therapeutic paradigm emerged for AD, namely the activation of the adaptive immune system directly against the self-peptide Ab, aimed at lowering its accumulation in the brain. This was the first time that a brain peptide was used to vaccinate human subjects in a manner similar to classic viral or bacterial vaccines. The vaccination approach has taken several forms, from initially active to passive and then back to modified active vaccines. As the first two approaches to date failed to show sufficient efficacy, the last is presently being evaluated in ongoing clinical trials. The present review summarizes the immunogenic characteristics of Ab in humans and mice and discusses past, present and future Ab-based immunotherapeutic approaches for AD. We emphasize potential pathogenic and beneficial roles of CD4 T cells in light of the pathogenesis and the general decline in T-cell responsiveness evident in the disease.

Autoimmune Manifestations in the 3xTg-AD Model of Alzheimer's Disease

“…In the case of 3xTg-AD mice, the transfer of human genes may result in excessive deposition of AΒ in peripheral tissues (amyloidosis), such as the spleen and liver. Chronic presentation of Aβ to over-reactive T cells may result in low-grade inflammation and autoimmune responses [91], likely aimed to clear the abundant protein [56, 92, 93]. The accompanying increase in serum levels of pro-inflammatory cytokines [94, 95] may compromise the integrity of the blood-brain barrier [96], accounting for cerebral amyloid angiopathy in AD patients and the 3xTg-AD model [97].…”

Interaction of astrocytes and T cells in physiological and pathological conditions

“…A number of reports suggest that some T cells are activated in AD patients, and that these cells exist both in the periphery and as infiltrates in the brain (Buckwalter et al, 2006; Monsonego et al, 2003; Monsonego et al, 2013; Trieb et al, 1996; Weiner and Frenkel, 2006). Immunization with Aβ in a mouse model of AD results in the accumulation of T cells at Aβ plaques in the brain (Fisher et al, 2010).…”

“…The characteristics of Aβ-specific T cells have yet to be thoroughly elucidated. It is proposed that Aβ may be presented to T cells via co-localized APCs including microglia and recruited blood APCs (Monsonego et al, 2013). However, whether astrocytes can uptake and present Aβ peptide remains unknown.…”

The Role of Inflammatory Mediators in the Pathogenesis of Alzheimer’s Disease

“…32 The amount of IFN-γ in the brain determines its effect as it is adverse at high levels and beneficial at low levels. 33 Research has demonstrated the pathogenic reaction of both T and B cells against Aβ as well as the risk of meningoencephalitis, caused by the entry of cluster of differentiation (CD) 8 cytotoxic T cells to the brain followed by the secretion of pro-inflammatory cytokines by CD4 T cells. 33,34 r o l e o f i n f l a m m at o r y c y t o k i n e s a n d c h e m o k i n e s There is growing evidence that inflammatory mediators in the CNS contribute to cognitive impairment through cytokine-mediated interactions between glial cells and neurons.…”

“…33 Research has demonstrated the pathogenic reaction of both T and B cells against Aβ as well as the risk of meningoencephalitis, caused by the entry of cluster of differentiation (CD) 8 cytotoxic T cells to the brain followed by the secretion of pro-inflammatory cytokines by CD4 T cells. 33,34 r o l e o f i n f l a m m at o r y c y t o k i n e s a n d c h e m o k i n e s There is growing evidence that inflammatory mediators in the CNS contribute to cognitive impairment through cytokine-mediated interactions between glial cells and neurons. Moreover, it has been demonstrated that AD is associated with the upregulation of proinflammatory cytokines, which can initiate plaque production and enhance nerve cell degeneration.…”