- Premise of this question is autoimmunity equals inflammation equals excessive TNF-a (Tumor Necrosis Factor-alpha) so blocking it should reduce autoimmunity-associated inflammation such as in MS (Multiple Sclerosis).
- Same idea occurred to people trying to develop therapies for MS as well.
- Big surprise because blocking TNF-a made Multiple Sclerosis (MS) worse, not better. Why?
Inflammation is part of normal human biology. When properly regulated, inflammation starts and stops when it should, and in between, it effectively and efficiently takes care of the problem that caused the inflammation in the first place, with minimal collateral damage to inflamed tissues and to the body.
When inflammation isn’t properly regulated as in autoimmune diseases such as MS, certain elements of the inflammatory process are out-of-sync, resulting in unsustainable tissue damage. However, the same therapy cannot treat different autoimmune diseases because the nature of the out-of-sync inflammatory process is unique to each autoimmune disease. In fact, current standard MS treatment is itself cytokines, namely, beta-interferons.
Thus, MS-associated inflammation is much more complicated than just ‘TNF-a is bad, let’s get rid of it and MS will improve‘. Clinical trials for MS that blocked TNF-a found worsening disease in patients. What happened? To understand, let’s start with why TNF-a was considered a potential target for MS, results of clinical trials that blocked TNF-a, and finally, possible reasons why TNF-a blockade made MS worse.
Why TNF-a was considered an attractive therapeutic target for MS
- TNF-a blockade works in other diseases (1): Reduces symptoms in other human autoimmune/inflammatory diseases such as Rheumatoid Arthritis (RA) and Inflammatory Bowel Disease (IBD), lending credence to the notion that it might reduce MS symptoms as well.
- TNF-a might disrupt the Blood-Brain Barrier (BBB): Studies in human MS (2) and rodent models (3) suggested TNF-a could damage/inhibit brain endothelial cells, thereby disrupting/damaging the Blood-Brain Barrier (BBB). BBB damage/leakage is considered a trigger for MS. So TNF-a could be involved in how MS starts.
- TNF-a accumulates in active MS lesions: TNF-a protein accumulates in active MS lesions (4, 5, 6). Could play a role in active MS disease.
- A TNF-a related gene polymorphism was identified as an MS risk factor: The TNFRSF1A gene encodes TNF Receptor 1 (TNFR1). Among many other immune-related genes, a GWAS (Genome-Wide Association Study; 7) identified a TNFR1 Single Nucleotide polymorphism (SNP) as MS-associated.
- Preclinical (non-human) MS animal models in rats and mice. Animals are induced to develop a disease called Experimental Autoimmune Encephalitis (EAE) that scientists claim recapitulates certain key features of MS such as demyelination of nerve fibers and limb paralysis.
- On the one hand, injecting TNF-a made EAE worse (8).
- OTOH, TNF-a neutralization through anti-TNF-a antibodies (9, 10, 11) or through a fusion protein designed to bind it (lenercept; a fusion protein consisting of the extracellular domain of TNFR1 fused to an IgG1 antibody) (12) reduced EAE.
- These results predicted that complete absence of TNF-a might reduce/prevent EAE in rodent models. However, TNF-a gene knockout mice also developed EAE (13). In other words, blocking TNF-a might not work in MS was a message hiding in plain hindsight.
Results of clinical trials that blocked TNF-a
- Open-label safety trial of anti-TNF antibody, infliximab, in 2 MS patients (14). Worse disease in both following treatment.
- 1-year placebo-controlled trial of lenercept (same biologic that worked in EAE) in 168 MS patients (15). Following 6 months of treatment, MS patients treated with lenercept had a dose-dependent increase in both severity and frequency of disease worsening and neurologic problems.
- TNF blockade also showed demyelination in some patients without MS (16, 17, 18, 19, 20). Currently, there are at least 7 different anti-TNF biologics and biosimilars, and all of them have been implicated in this inflammatory demyelination. Implication? Demyelination is a generalizable feature of TNF-a blockade, and not attributable to off-target effect of any one particular anti-TNF biologic.
How could TNF-a blockade make MS worse
Preclinical models are not good mimics of human MS. Eminent physicians such as
TNF-a is neuroprotective, at least in MS. TNF-a is a cytokine. As such, when secreted by a cell, its effects ensue from binding its specific receptors on cells.
- Turns out the MS-associated SNP (Single Nucleotide Polymorphism) in the TNF receptor 1 (TNFR1) gene (7) results in a novel form of the TNF receptor called TNFRSF1A, which binds TNF-a extracellularly (22).
- This risk variant of the SNP, rs1800693, named Delta6-TNFR1, promotes splicing out of TNFR1 exon 6. The resulting protein comprises most of the extracellular domain of TNFR1 plus a short novel tail, but no transmembrane or cytoplasmic domains. Soluble i.e. secreted, rather than expressed on the cell surface, Delta6-TNFR1 can bind (immobilized) TNF-a, and neutralize its signaling, preventing/reducing its normal biological activity, activity that would normally ensue from TNF-a binding to its cell-surface, not soluble, receptor.
- This SNP variant is associated with MS but not RA, IBD or psoriasis (23). This may be why TNF-a blockade works in the latter but not in MS.
- TNF-a blockers used in MS apparently mimic the effect of this soluble receptor. Such results imply that, rather than playing a role in MS inflammation, TNF-a may counteract the damaging immune response. Antibodies that block TNF-a thus block TNF-a’s protective effect against the damaging immune response in MS.
Thus, TNF-a can have either neuroprotective or neurotoxic effect depending on the signaling pathway that dominates after it binds its receptors, and human clinical data suggests at least in MS, it is neuroprotective (24, 25).
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