T-cell based immunotherapies for Parkinson’s disease

Rodrigo Pacheco

doi:10.37349/ent.2021.00007

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.

Highlights

Parkinson’s disease is a neurodegenerative disorder that affect mainly the dopaminergic neurons of the nigrostriatal pathway
With regard to the presence of T-cell epitopes in unmodified αSyn, Davtyan and colleagues [38] evaluated the activation of T-cells in C57BL/6 mice immunized with a battery of overlapping peptides obtained from the aminoacidic sequence of unmodified αSyn, and they found only the αSyn76-95 and the αSyn106-125 peptides were able to induce IFN-γ production by T-cells. Taken together these results indicate that, compared with unmodified αSyn, pathogenic forms of αSyn contains different T-cell epitopes, an important point to be considered at the moment of developing T-cell mediated immunotherapies geared to target selectively only pathogenic forms of αSyn, but not healthy αSyn
According to the poor histocompatibility leukocyte antigens (HLA) restriction of the C-terminus antigenic region of the hαSyn, a recent study performed with six Parkinson’s disease patients revealed that the T-cell receptor (TCR) repertoire of αSyn-specific T-cells was as diverse as the TCR repertoire of T-cells specific for pertussis, a representative foreign antigen that most individuals have been exposed to [40]. These results provide evidence that pathogenic forms of αSyn contain epitopes recognized by autoreactive T-cells, some of them strongly restricted by HLA alleles and others just poorly dependent of HLA alleles (Figure 2)

Summary

Introduction

Parkinson’s disease is a neurodegenerative disorder that affect mainly the dopaminergic neurons of the nigrostriatal pathway Since these neurons are involved in the control of voluntary movement, the most characteristic symptom associated to this pathology is a motor impairment, including bradykinesia, postural instability, tremors, and rigidity. This disorder involves the generation of pathogenic protein inclusions in the brain, which are composed mainly by a pre-synaptic protein called α-synuclein (αSyn) [1]. Microglial cells are the central players in this neuroinflammatory process In this regard, it has been described that initial microglial activation is triggered by pathogenic forms of αSyn, which stimulate toll-like receptors (TLRs) on these cells [4, 5]. The acquisition of a particular functional phenotype by microglia might define the development of neuroinflammation and the consequent neurodegeneration in Parkinson’s disease

Objectives

Conclusion