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Vaccination against Alzheimer disease: hope renewed
4 November 2002
by Martin F. Bachmann
martin.bachmann@cytos.com
Hock C et al. (2002). Generation of antibodies specific
for beta-amyloid by vaccination of patients with Alzheimer disease.
Nat Med - Published online before print.
Alzheimer disease is characterized by progressive dementia
probably caused by accumulation of amyloid plaques in the brains of
afflicted people. These plaques essentially consist of peptides
(A-beta1-40/42) derived from the amyloid precursor
protein (APP). At the present time there is little symptomatic
treatment and no curative therapy available, which makes Alzheimer
disease one of the most distressing illnesses both for the patients
and their families.
A ray of hope for a foreseeable therapy was provided recently by
vaccination experiments in transgenic mice. Specifically, mice
expressing mutant forms of human APP efficiently cleaved into A-beta1-40/42-peptides
were shown to develop Alzheimer disease-like pathology. To the great
surprise of the field, both plaque burden and dementia could be
reduced in these mice by active immunization for antibody induction
using A-beta1-40/42 formulated in QS-21 as a vaccine
(AN1792). Although the mechanism of plaque removal remains unclear,
vaccination has proved to be efficient in a variety of
APP-transgenic mouse models. Progress towards the clinic was rapid
and ELAN pharmaceuticals, the front runner in the field, initiated a
Phase II trial designed to demonstrate efficacy of the therapy also
in humans. However, it was this particular study that brought hopes
and progress to an abrupt halt, because a few treated patients
developed signs of aseptic encephalitis/meningitis following the
second administration of the vaccine. Although little information
has been released publicly, the disease-symptoms were consistent
with induction of autoimmunity, an inherent risk and concern when
vaccinating against self-antigens such as A-beta1-40/42.
Hence, this trial has been stopped.
A detailed understanding of the immune responses induced in the
vaccinated individuals is now critical for further development of
vaccination strategies that avoid these severe (albeit treatable)
side-effects. It is of particular importance to understand the
origin of the vaccine-induced disease, namely whether it was
non-specifically caused by the adjuvants used, or the antibodies
were precipitating inflammation or whether A-beta1-40/42-specific
T cells were responsible for the side-effects.
Thankfully, the study by the group of Nitsch now offers the first
insights into these questions. Of the 24 patients vaccinated in the
study center in Zürich, almost all raised a significant antibody
response. In addition, the antibodies recognized plaques of
transgenic mice and patients, a requirement for plaque-removal in
the mouse model. However, aseptic encephalitis/meningitis developed
in one individual. Intriguingly, this particular patient had only
raised a moderate antibody response. This observation indicates that
specific antibodies alone might not be sufficient to cause disease
in Alzheimer patients. Furthermore, the results are compatible with
the view that T cells, rather than antibodies, are the major source
of inflammation. This hypothesis is consistent with the fact that
most, if not all, known inflammatory responses in the brain are
caused by T cells rather than antibodies.
Although it is obviously impossible to draw firm conclusions from
a single patient, the data nevertheless suggest that vaccines
against Alzheimer disease should aim at circumventing the induction
of inflammatory T cell responses. Indeed, avoiding the use of
adjuvants and restricting the size of the epitopes used for
vaccination could offer valuable solutions for the generation of a
viable vaccine against one of the most devastating diseases
afflicting mankind. |
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See also:
Therapeutic vaccines: realities of today and hopes for the future
Michael Sela michael.sela@weizmann.ac.il, Ruth Arnon and Bilha
Schechter (2002) Drug Discovery Today 7:664-673.
Novel therapeutic strategies provide the real test for the amyloid
hypothesis of Alzheimer's disease
Diana Ines Dominguez and Bart De Strooper (2002) Trends in
Pharmacological Sciences 23:324-330.
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