Objective/Rationale:
Evidence in humans and in research models support a role for the immune system in the progression of Parkinson's disease. Local brain immune cells, called microglia, as well as circulating blood immune cells, such as T cells, have been shown to be activated during the neurodegenerative process. Our project will focus on the interplay between circulating and local immune cells, to use their possible inter-modulation as a therapeutic tool to protect neurons in the disease.
Project Description:
In the project we will first study how to predispose blood T cells towards a protective status that in turn can interact with brain microglial cells to enhance their neuroprotective profile. This strategy will be confirmed in vivo by transplanting such conditioned blood cells into a preclinical model of PD, which is based on accumulation of the protein alpha-synuclein in the midbrain. These models will be followed behaviorally and studied anatomically to determine if the transplanted blood cells redirect brain microglia towards a protective status, that would, in turn, result in neuronal protection.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Therapies based on enhancing and/or modulating T cell function are already being tested in patients afflicted with different inflammatory diseases. These cells are ideal therapeutic tools since they can be modulated in the periphery by drugs already in use; and can be easily harvested form the patients themselves to be primed in vitro before autologous transplantation. If successful, our project will open a novel therapeutic approach in humans that can benefit from knowledge already acquired in other fields, therefore accelerating its future use in patients.
Anticipated Outcome:
We anticipate that our project will bring understanding to how the peripheral adaptive immune system (T cells) interacts with the brain resident immune system (microglia), and that this knowledge will permit us to stop or modulate the adverse immune processes that contribute to Parkinson's disease. Such knowledge will further help develop strategies where, with drugs already in use, we can modify the detrimental processes happening in the brain from outside of the brain.
Final Outcome
We have characterized the effect alpha-synuclein has on the peripheral immune system, specially the effect it has T cells. We looked at different doses and types of alpha-synuclein, and found that the type of alpha-synuclein is not important but the dose was crucial to induce a change in the immune cell’s activation patterns. At high dose those cells that are in charged of protecting us from autoimmune inflammation (Treg) loose their ability to home to the brain. Importantly we show that by affecting the peripheral immune system we can change the type of activation of the brain’s immune cells, microglia. As microglia are responsible for chronic inflammation in brain, this may prove very productive for designing future therapeutic tools. We are currently activating Treg in a specific manner and transplanting them into an alpha-synuclein based pre-clinical model of PD to determine their ability to stop neuroinflammation and protect neurons from cell death.