4 November 2002

by Martin F. Bachmann martin.bachmann@cytos.com
 

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-beta_1-40/42) 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-beta_1-40/42-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-beta_1-40/42 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-beta_1-40/42. 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-beta_1-40/42-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.