Welcome to the IBRO 2023 Interactive Programme

Abstract Body

Over the last two decades, my team initiated a change in understanding of the brain-immune relationships, by demonstrating that the brain requires support from innate and adaptive immune cells for its maintenance and repair. Deep understanding of these relationships by our team and by others has led us to propose that the immune cells that are hosted within the brain's borders, together with neurons and non-neuronal cells, form an ecosystem that enhances the resilience of the brain and its robustness in withstanding continuous and diverse perturbations. Accordingly, any dysfunction in this brain-immune communication might impact brain activity. As aging is the major risk factor in dementia, including Alzheimer’s disease, we propose that dysfunction of any aspect of the brain-immune ecosystem could affect disease onset and severity, but could be amenable to immune intervention. This model led us to propose that defeating such diseases could be accomplished by harnessing the immune system, which is either exhausted or insufficient. We found that transiently blocking the inhibitory PD-1/PD-L1 immune checkpoint pathway, initiates an immune response in the periphery that leads to disease modification within the brain. This approach was found to be effective regardless of disease etiology, and is independent of microglial polymorphism. We found that the treatment improved cognitive performance and reduced multiple parameters that contribute to disease escalation, including neural loss, local inflammation, and phospho- and aggregated-tau in tauopathy, and soluble oligomers of amyloid beta in amyloidosis. The effect was found to be dependent on bone marrow-derived macrophages, and was also associated with homing of FoxP3 regulatory T cells. Brief intermittent treatment with an AD-optimized antibody was found to provide long-term effect. Together, these studies show that targeting the immune system provides new avenues for understanding and treating neurodegenerative diseases.