Can Immunotherapy Treat CNS Disease?

Neuroimmunology, immunopsychiatry and the cusp of a new era in treating diseases of the central nervous system

Neuroimmunology is a discipline encompassing both the fields of neuroscience and immunology. The immunologically privileged status of the central nervous system has now been revoked, and the neuroimmune system is currently understood to comprise of microglia, astrocytes, oligodendrocytes, mast cells and furthermore macrophages and T cells.

Recent epidemiological evidence suggests that infection (either direct or maternal), autoimmune disease, and environmental factors affecting the immunoinflammatory system are all implicated in the etiology, physiopathology and comorbidity of several psychiatric conditions including schizophrenia, autism (ASD), and Alzheimer’s disease (AD). Pro-inflammatory cytokines directly modulate neural targets controlling behavior, sleep, and mood. These observations are leading to the emergence of a new speciality referred to as immuno-psychiatry, where peripheral immune mechanisms govern behaviors and emotions.

NMDA receptors (N-methyl D-aspartate, receptors to glutamate) are a promising target for neuro-immunotherapies. These proteins are strongly implicated in excitotoxicity, and pathological process at the root of many neurodegenerative disorders. A monoclonal antibody targeting a regulatory site of the NMDA-R, Glunomab, reverts the effect of tissue plasminogen activator without affecting the receptor activity, reducing the progression of neurological impairment during experimental autoimmune encephalomyelitis and abridging the migration of leukocytes through the blood-brain barrier. These observations position Glunomab and similar antibodies as promising candidates in the treatment of multiple sclerosis (MS).

Interestingly, auto-antibodies against NMDA receptor extracellular epitopes have been detected in psychosis disorders. Memantine, a NMDA receptor blocker prescribed to AD patients, has been successfully used in schizophrenic patients to improve negative and cognitive symptoms. In addition, aspirin and non-steroidal anti-inflammatory drugs prescribed alongside antipsychotic therapy have also been shown to reduce positive and negative symptoms of schizophrenic patients.

Autism is a neurodevelopmental disorder of unknown etiology. Disrupted immune function has been reported, with low immunoglobulin levels, low T cells numbers, altered cytokine expression and disrupted NK cell function. Epidemiologic studies have unveiled a correlation between ASD and a family history of autoimmune diseases. Specific clusters of immune genes of the MHC have been implicated in ASD. Remarkably, the human variant GRINB2 gene encoding GluN2B NMDA receptor is implicated in ASD as well as other psychiatric conditions including attention deficit hyperactivity disorder and schizophrenia.

Clinical studies have exposed an association between obsessive compulsive disorder (OCD), Tourette’s syndrome (TS) (and its pediatric equivalent, PANDAS – pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection) and immune responses to pathogens such as group A Streptococcus. Exposure to the pathogens leads to a pathological autoimmune response where strep-related antibodies cross a damaged-blood-brain barrier and bind to specific targets in the basal ganglia, affecting neural targets involved in motion control. Immunotherapy trials using intravenous immunoglobulins on patients have been promising, although limited in time and sample size.

In addition to the huge potential of focusing on the immunological and inflammatory aspects of psychological disorders as a means of identifying new targets, there is a clear role that these disciplines can play by including inflammatory biomarker analysis, gut-brain axis health, and autoantibody expression in establishing novel immuno-psychiatric diagnostics. Current diagnosis is based solely on symptoms and observable signs and is often protracted due to difficulties in defining the precise disorder. This leaves patients and their families with uncertainty and delays the implementation of the most appropriate treatments with antipsychotics or antidepressants.

It is therefore clear that neuroimmunology and immunopsychiatry are at the dawn of a new era for diagnosis and treatment.

Discovery

Aug 07, 2018 |
Sylvie Hunt

Can Immunotherapy Treat CNS Disease?

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