Abstract
TNF has as detrimental role in multiple sclerosis (MS), however, anti-TNF medication is not working. Selective TNF/TNFR1 inhibition whilst sparing TNFR2 signaling reduces the pro-inflammatory effects of TNF but preserves the important neuroprotective signals via TNFR2. We previously reported the generation of a Nanobody-based selective inhibitor of human TNFR1, TROS that will be tested in experimental autoimmune encephalomyelitis (EAE). We specifically antagonized TNF/TNFR1 signaling using TROS in a murine model of MS, namely MOG35-55-induced EAE. Because TROS does not cross-react with mouse TNFR1, we generated mice expressing human TNFR1 in a mouse TNFR1-knockout background (hTNFR1 Tg), and we determined biodistribution of 99mTc-TROS and effectiveness of TROS in EAE in those mice. Biodistribution analysis demonstrated that intraperitoneally injected TROS is retained more in organs of hTNFR1 Tg mice compared to wild type mice. TROS was also detected in the cerebrospinal fluid (CSF) of hTNFR1 Tg mice. Prophylactic TROS administration significantly delayed disease onset and ameliorated its symptoms. Moreover, treatment initiated early after disease onset prevented further disease development. TROS reduced spinal cord inflammation and neuroinflammation, and preserved myelin and neurons. Collectively, our data illustrate that TNFR1 is a promising therapeutic target in MS.
Highlights
Tumor necrosis factor (TNF) is detrimental in several chronic inflammatory diseases such as rheumatoid arthritis (RA), inflammatory bowel disease (IBD) and psoriasis
We previously reported on the generation of the trivalent Nanobody called TROS that binds and inhibits human TNF receptor 1 (TNFR1), but without cross-reactivity to mouse TNFR1
The hTNFR1 Tg mice express human TNFR1 and, it has previously been shown that murine TNF can interact with human TNFR127, we found solid evidence that our hTNFR1 Tg mice effectively respond to murine TNF
Summary
Tumor necrosis factor (TNF) is detrimental in several chronic inflammatory diseases such as rheumatoid arthritis (RA), inflammatory bowel disease (IBD) and psoriasis This has led to scientific breakthroughs and to the development of several TNF inhibitors. Patients who received anti-TNF medication for other diseases sporadically developed neurological symptoms and lesions with demyelination[16] These data indicate that TNF has pathogenic roles but is essential in maintaining immune homeostasis in the CNS environment. A neuroprotective role is attributed to TNFR2 because its signaling protects neurons against excitotoxic insults, and promotes neuronal survival, oligodendrocyte regeneration and CNS remyelination[3,19,20,21,22,23,24] These data show that TNFR1 is a potential target in the pathogenesis of MS whereas the TNFR2 should be preserved. Our data support that TNFR1 is a valuable therapeutic target in MS
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