T-cell based immunotherapies for Parkinson’s disease

Abstract

Current evidence indicates that neurodegeneration of dopaminergic neurons of the substantia nigra associated to Parkinson’s disease is a consequence of a neuroinflammatory process in which microglial cells play a central role. The initial activation of microglial cells is triggered by pathogenic protein inclusions, which are mainly composed by α-synuclein. Importantly, these pathogenic forms of α-synuclein subsequently induce a T-cell-mediated autoimmune response to dopaminergic neurons. Depending on their functional phenotype, these autoreactive T-cells might shape the functional features of activated microglia. T-cells bearing pro-inflammatory phenotypes such as T-helper (Th)1 or Th17 promote a chronic inflammatory behaviour on microglia, whilst anti-inflammatory T-cells, such as regulatory T-cells (Treg) favour the acquisition of neuroprotective features by microglia. Thus, T-cells play a fundamental role in the development of neuroinflammation and neurodegeneration involved in Parkinson’s disease. This review summarizes the evidence indicating that not only CD4+ T-cells, but also CD8+ T-cells play an important role in the physiopathology of Parkinson’s disease. Next, this review analyses the different T-cell epitopes derived from the pathogenic forms of α-synuclein involved in the autoimmune response associated to Parkinson’s disease in animal models and humans. It also summarizes the requirement of specific alleles of major histocompatibility complexes (MHC) class I and class II necessaries for the presentation of CD8+ and CD4+ T-cell epitopes from the pathogenic forms of α-synuclein in both humans and animal models. Finally, this work summarizes and discusses a number of experimental immunotherapies that aim to strengthen the Treg response or to dampen the inflammatory T-cell response as a therapeutic approach in animal models of Parkinson’s disease.

Role of neuroinflammation in neurodegeneration development

“…Some studies have attempted to increase Treg responses. 576 But all these studies were done in PD animal model. In the future, clinical trials are needed to further verify the effectiveness of these kinds of therapeutic methods.…”

Lewy Body Formation through the lens of Cytokine-Mediated Neuroinflammation in Parkinson's Disease Development

“…Additionally, IFN-γ suppresses the expression of neurotrophic factors critical for neuronal survival and function, such as brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), further compromising neuronal viability and plasticity. Dysregulated synaptic function, induced by IFN-γ, disrupts neuronal communication and network activity, leading to synaptic dysfunction and neuronal hyperexcitability, ultimately contributing to neuronal instability and susceptibility to injury [115].…”

“…Moreover, IFN-γ contributes to oxidative stress by stimulating the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) within neurons and glial cells. This excessive generation of ROS/RNS overwhelms cellular antioxidant defenses, leading to oxidative damage to lipids, proteins, and DNA, impairing neuronal function and viability [115]. Additionally, IFN-γ disrupts mitochondrial function in neurons, further exacerbating neuronal injury and cell death.…”