Tumor Necrosis Factor Alpha Blockade and Multiple Sclerosis: Exploring New Avenues

Abstract

Multiple sclerosis (MS) is the most common disabling disease of the central nervous system (CNS) with a progressive neurodegenerative pattern. It is characterized by demyelination of white matter in CNS and apoptosis of oligodendrocytes. Tumor necrosis factor (TNF) alpha is a major cytokine in the pathogenesis of MS. However, the failure of TNF alpha inhibitors in preclinical and clinical trials disapproved of their use in MS patients. Nevertheless, failures and misses sometimes open avenues for new hits. In the later years, it was discovered that TNF signaling is mediated via two different receptors, TNFR1 and TNFR2, both of which have paradoxical effects. TNFR1 mediates demyelination and apoptosis, while TNFR2 promotes remyelination and neuroprotection. This explained the cause of the failure of non-selective TNF alphablockers in MS. It also enlightened researchers that repurposing the previously formulated non-selective TNF alpha-blockers using a receptor-selective approach could lead to discovering novel biologic agents with a broader spectrum of indications and better safety profiles. This review focuses on a novel premier TNFR1 blocker, atrosab, which has been tested in animal models of MS, experimental autoimmune encephalomyelitis (EAE), where it demonstrated a reduction in symptom severity. The early promise shown by atrosab in preclinical studies has given us hope to find another revolutionary drug for MS in the future. Clinical trials, which will finally decide whether this drug can be used as a better therapeutic agent for MS or not, are still going on, but currently, there is no approved evidence regarding efficacy of these agents in treating MS.

Acute Neurological Involvement after Donor Lymphocyte Infusion for Post-Transplant Viral Infection: The Same Pattern of Novel Cancer Immunotherapy-Related CNS Toxicity?

“…In particular, this result has been confirmed in neurodegenerative diseases such as Alzheimer’s and multiple sclerosis, characterized by serious cognitive disabilities. Under these conditions, the new neuroprotective pharmacological strategy is based on the inhibition of TNF-α, which, according to the results collected, seems to have a protective effect on patients with mild cognitive deterioration by counteracting inflammation [ 32 , 33 , 34 ].…”

Past, Present and (Foreseeable) Future of Biological Anti-TNF Alpha Therapy

“…The demyelination of the central and peripheral nervous system was reported more frequently after 17 months of treatment, although the causal association with anti-TNF-α therapy is still uncertain [ 92 , 93 ]. Indeed, the use of TNF-α inhibitors in patients with multiple sclerosis has showed a worsening of the disease [ 94 , 95 , 96 ]. To date, there are no guidelines for the management of patients who manifest this complication, and only the suspension of TNF-α inhibitors and the administration of high-dose corticosteroids are recommended [ 97 ].…”

A common mechanism links Epstein‐Barr virus infections and autoimmune diseases

“…[17][18][19][20] LMP1 functions as an inflammation-promoting factor, at least by inducing a panel of proinflammatory cytokines, some of which are clearly associated with autoimmunity. 19,[21][22][23] Second, acute EBV infections in mononucleosis generate a wave of cytokines and chemokines including interleukin 1 beta (IL-1β), IL-1 receptor antagonist (IL-1Ra), IL-6, IL-8, IL-18, tumor necrosis factor-α, interferon alpha/beta (IFN-α/β), IFN-γ, monokine induced by IFN-γ (Mig), IFN-γ-inducible protein 10 (IP-10) and granulocyte macrophage colony-stimulating factor (GM-CSF) (reviewed in. 24 During persistent phase, EBV infections of human naïve B-lymphocytes are predicted to produce the similar but less amounts of cytokines in vivo because EBV-specific CTLs will be present and functional (Figure 1A).…”