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I.R.F. / Aging news / Diseases / 03100701

Alzheimer's Disease, Immunization, T Cell Response and Beta Amyloid
Posted on: October 7, 2003

Alzheimer disease (AD) is the most common form of age-related cognitive failure in humans. It is characterized by the progressive accumulation of the amyloid β protein (Aβ) in limbic and association cortices, where some of it precipitates to form a range of amorphous and compacted (fibrillar) extracellular plaques. These plaques, particularly the more compacted ones, are associated with dystrophic neurites (altered axons and dendrites), activated microglia, and reactive astrocytes. Cleavage of the amyloid precursor protein (APP) by the β and γ secretases releases both the Aβ1-40 and Aβ1-42 peptides, the latter being far more prone to aggregation and induction of neurotoxicity.

AD has received a lot of recent attention, particularly in areas related to novel treatments. Recently, the potential therapeutic usefulness of the immune system has become apparent, leading to the question of whether it can be used to directly or indirectly influence AD-related pathology in beneficial ways. Active immunization with amyloid β (Aβ) peptides takes advantage of the immune system to generate antibodies that can somehow decrease Aβ-related pathology in mouse models of AD. Similarly, passive immunization involves direct administration of anti-Aβ antibodies, bypassing the need for an active immune response. Since genetic, pathologic, and animal studies suggest that the buildup of Aβ in the brain leads directly or indirectly to cell dysfunction, cell death, and cognitive impairment, increased generation of anti-Aβ antibodies has the potential to prevent or treat AD by decreasing amyloid burden and its consequences in the brain. Though the first clinical trials for Aβ vaccination were halted due to CNS inflammation in a small subset of subjects, active and passive immunization strategies remain a viable potential therapy worth continued exploration. If positive effects can be seen in future trials, it will be important to minimize unwanted toxicity.

Inflammation may play an important role in mediating the neuronal and glial alterations that occur in AD. Evidence to date has suggested that this inflammation arises mainly from within the CNS. However, a recent study showed increased occurrence of T cells in the brains of patients with AD as compared with subjects with non-AD degenerative dementias and aged-matched controls. The inflammatory changes - including microgliosis, astrocytosis, complement activation, cytokine elevation, and acute phase protein changes - are thought to represent, at least in part, a response to the early accumulation of Aβ1-42 in the brain. Although AD is thus associated with local innate immune responses, the induction of systemic adaptive immune responses to Aβ in mouse models of AD has been found to be beneficial for both the neuropathological and behavioral changes that these mice develop. However, a human clinical trial in which an Aβ1-42 synthetic peptide was administered parenterally to patients with AD was discontinued when approximately 5% of 300 treated patients developed what appeared to be a self-limited aseptic meningoencephalitis. The cause of this reaction is unknown, but one of the major hypotheses is that an immune reaction to Aβ was responsible.

Self-reactive T cells of low-to-moderate binding affinity are not necessarily deleted during negative selection in the thymus, and some autoreactive T cells are positively selected and maintain the normal immune repertoire. Although such autoreactive T cells can mediate autoimmune diseases, they may also play a beneficial physiological role in immune regulation and maintenance of normal tissues. Furthermore, although the CNS has been described as immunologically privileged, it is now known that activated T cells can routinely penetrate the CNS. Although Aβ-reactive B cells were previously observed in patients with AD, the presence of T cell reactivity to Aβ has not been previously described in patients with AD or shown to be related to the aging process. Because Aβ antigen is progressively deposited in the CNS with age and in AD, might be that T cell reactivity to Aβ could either decrease or increase with aging and in patients with AD, depending on whether the peptide was tolerogenic or immunogenic. Furthermore, the nature and magnitude of T cell reactivity to Aβ in humans could have either beneficial or injurious effects for the host and may have important implications for Aβ vaccination strategies in AD.

Some healthy, elderly individuals, as well as individuals with AD, contain elevated baseline levels of Aβ-reactive T cells. While the general trend is toward a diminished immune response with aging, this demonstrates a selective increase in Aβ-reactive T cells in older individuals with and without dementia. The reason for this selective expansion of Aβ-reactive T cells in elderly individuals remains unclear. It is often presumed that cognitively normal middle-aged and elderly individuals are similar in that they lack AD pathology; however, Aβ deposition in plaques appears to begin about 10-20 years prior to the onset of even the earliest symptoms suggestive of dementia due to AD. This means that some cognitively normal elderly subjects in this study likely possessed aggregated Aβ deposits in the brain, while it is also likely that most middle-aged individuals (younger than age 50) did not have AD pathology. One interesting possibility is that this change in T cell population is a response to the presence of Aβ aggregates even in the absence of dementia. The conformation of aggregated Aβ in AD is predominantly as β-sheets, whereas the soluble Aβ present in blood and cerebral spinal fluid has little or no β-sheet structure. Perhaps, this conformational change in endogenous Aβ stimulates a T cell response.

Circulating Aβ-reactive T cells are present in patients with AD and increase with aging. It is unknown why Aβ-reactive T cells are maintained throughout life and why they increase in the elderly and in patients with AD in the face of decreasing T cell priming that occurs with aging. Aβ1-42 is a self-antigen, and self-reactive T cells have been implicated in variety of activities, such as immune regulation, self-maintenance and repair, and autoimmune diseases. Aβ-reactive T cells were detected in almost all subjects tested, suggesting that these cells either escape central and peripheral tolerance or are positively selected to maintain the normal T cell repertoire. It is possible that the activation and expansion of Aβ-reactive T cells in the elderly and patients with AD indicates that Aβ is captured in the brain in the context of Aβ deposition, and migrate to secondary lymph nodes and induce T cell activation. Although Aβ deposition occurs in elderly humans that do not have overt signs of AD, there appears to be increased T cell reactivity to Aβ in patients with AD, since in contrast to elderly subjects, all patients with AD tested had some Aβ reactivity. Such reactivity could reflect an endogenous reaction to Aβ deposition in the brain in the context of the local innate immune response that occurs in AD.

In a recent Aβ vaccination trial, some patients with AD developed brain inflammation, hypothesized to be due to induced T cell responses. On the basis of the findings of endogenous reactivity to Aβ in patients with AD, the use of a full-length Aβ peptide and might be expected, in retrospect, to lead to T cell-mediated CNS inflammatory effects, particularly in patients with AD having a preexisting high frequency of Aβ-reactive T cells. Aβ administered intranasally to APP transgenic mice induced anti- Aβ antibodies and partial clearance of Aβ plaques, accompanied by infiltration into the CNS of small numbers of mononuclear cells expressing the anti-inflammatory cytokines IL-4, IL-10, and TGF-β. Since almost all human Aβ-reactive T cell lines studied also showed a cytokine phenotype, it is possible that mucosal immunization could boost this lineage and thus enhance clearance of Aβ by both stimulating Aβ antibody production and modulating microglial activation at sites of Aβ plaques, with a minimal risk of harmful T cell responses in the CNS.

In addition to the clear relevance of findings of intrinsic Aβ T cell reactivity for vaccination strategies in AD, the increased responses to Aβ scientists observed with age may be an important link to physiological immune responses to Aβ that may have either beneficial or harmful effects for the host. Given that T cell immunity tends to decrease with age, the increased reactivity to Aβ observed may represent an unusual immunologic response that could provide insights into the aging process and its relationship to Aβ. Now it is evident that a number of FDA-approved nonsteroidal anti-inflammatory drugs are capable of lowering Aβ levels in mice. It suggests that further testing of the therapeutic utility of these types of compounds for the potential treatment of AD is warranted.

Source 1: Alon Monsonego, Victor Zota, Arnon Karni, Jeffery I. Krieger, Amit Bar-Or, Gal Bitan, Andrew E. Budson, Reisa Sperling, Dennis J. Selkoe, and Howard L. Weiner; Increased T cell reactivity to amyloid β protein in older humans and patients with Alzheimer disease. J. Clin. Invest. August 2003, Volume 112, Number 3, pp 415-422
Source 2: John R. Cirrito and David M. Holtzman; Amyloid . and Alzheimer disease therapeutics: the devil may be in the details. J. Clin. Invest. August 2003, volume 112, number 3, pp 321-323.
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