This academic research study will examine how the first experimental therapeutic vaccine, designed to reduce brain accumulation of amyloid in Alzheimer’s disease, caused a life-threatening inflammatory response in some of the patients participating in the initial clinical trial sponsored by the vaccine’s pharmaceutical company developer. The findings could help guide future development of Alzheimer’s therapies that avoid this serious, and sometimes deadly, inflammatory complication.
Alzheimer’s disease is characterized by accumulation in the brain of the protein called amyloid. A pharmaceutical company recently developed a therapeutic vaccine designed to reduce the build-up of amyloid. Animal studies indicated that the small amount of amyloid contained in the vaccine stimulated the animals’ immune systems to attack amyloid when they subsequently encountered it in the brain. Based on the animal testing, the Food and Drug Administration approved a small clinical trial of vaccine in 16 Alzheimer’s patients to determine the vaccine’s relative safety and assess initial indications of its efficacy. Some vaccine recipients showed evidence of slower rates of cognitive clinical decline compared to untreated patients.
The trial was abruptly halted, however, when five percent of the patients developed life-threatening meningoencephalitis, a devastating inflammation in the brain. One of these patients died. An autopsy of this patient’s brain showed decreased amounts of amyloid, compared to the amount usually found at autopsy of Alzheimer’s patients. This patient’s autopsy also showed evidence that a large number of immune T cells had been activated.
These autopsy findings have prompted Harvard researchers to develop a new mouse model that, when imaged, will help in understanding the interaction between the therapeutic vaccine and the immune T cells’ production of a massive inflammatory response. While the vaccine is designed to stimulate production of immune T cells to attack the amyloid, it is not clear why the T cells produced the large inflammatory response. The Harvard researchers' new animal model will try to help address that question.
The investigators have developed a fluorescent compound to label immune T cells, and the T cells’ actions that occur in Alzheimer’s disease in response to the experimental vaccine now can be viewed using microscopy in a new animal model. The animal model was produced by breeding a mouse model of Alzheimer’s disease with a strain of mice in which specific subpopulations of immune T cells have been engineered to contain fluorescent proteins. This resultant new Alzheimer’s disease mouse model has T cells that will fluoresce, providing direct visualization of the animals’ immune T cells in different states of activation. The imaging also will show the fluoresced interaction between the animals’ immune T cells and the antibodies that are stimulated by the vaccine. This new model is expected to help determine what went wrong in use of the experimental vaccine. Eventually, this “fluoresced” animal model of Alzheimer’s disease should be able to be used to study the effects of future experimental therapies that are intended to modify the immune system’s response to immunizations designed to reduce amyloid accumulation.
Significance: This new animal model that allows visualization of fluorescently labeled immune T cell subpopulations may help to reveal how experimental therapeutic immunization to reduce amyloid deposits in Alzheimer’s produces a deadly T cell inflammatory response. By understanding this harmful immune response, the results may provide new insights into future development of therapies that avoid this consequence. The animal model and technique will provide a means of determining the effects on immune T cells of such future experimental therapeutic vaccines.