Fingolimod therapy is not effective in a mouse model of spontaneous autoimmune peripheral polyneuropathy

Petra Huehnchen,Matthias Endres,Wolfgang Boehmerle

doi:10.1038/s41598-018-23949-4

Abstract

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an autoimmune disorder, which causes progressive sensory and motor deficits and often results in severe disability. Knockout of the co-stimulatory protein CD86 in mice of the non-obese diabetic background (NoD.129S4-Cd86tm1Shr/JbsJ) results in the development of a spontaneous autoimmune peripheral polyneuropathy (SAPP). We used this previously described transgenic model to study the effects of the sphingosine-1-phosphate receptor agonist fingolimod on SAPP symptoms, functional and electrophysiological characteristics. Compared to two control strains, knockout of CD86 in NOD mice (CD86−/− NOD) resulted in progressive paralysis with distinct locomotor deficits due to a severe sensory-motor axonal-demyelinating polyneuropathy as assessed by electrophysiological measurements. We started fingolimod treatment when CD86−/− NOD mice showed signs of unilateral hind limb weakness and continued at a dose of 1 mg/kg/day for eight weeks. We did not observe any beneficial effects of fingolimod regarding disease progression. In addition, fingolimod did not influence the functional outcome of CD86−/− NOD mice compared to vehicle treatment nor any of the electrophysiological characteristics. In summary, we show that fingolimod treatment has no beneficial effects in autoimmune polyneuropathy, which is in line with recent clinical data obtained in CIDP patients.

Highlights

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is the most common treatable autoimmune neuropathy[1]
CD86−/− non-obese diabetic (NOD) mice showed a significant increase in F-wave latency of the sciatic nerve by 40% ± 7% (2-way ANOVA, F(2,72) = 8.632, p < 0.0001; Fig. 1F) and a decrease of the sensory conduction velocity (SCV) and sensory nerve action potential (SNAP) amplitude (both Kruskal-Wallis test, p < 0.0001 (SCV) and p < 0.0239 (SNAP); Fig. 1G,H)
None of the control mice showed signs of neuropathy. (C) Paralysis steadily progressed in CD86−/− NOD mice until all mice had to be sacrificed according to humane endpoints by 32 weeks of age when reaching a clinical score of >3.5. (D) We did not observe any signs of mechanical hypersensitivity in any of the mice, while (E) locomotor function significantly decreased in CD86−/− NOD mice over time. (F) In parallel, CD86−/− NOD mice developed a significant increase of the F-wave latency of the sciatic nerve. (G) The sensory nerve conduction velocity (SCV) as well as (H) the sensory nerve action potential amplitude (SNAP) of the tail nerve decreased in CD86−/− NOD mice

Summary

Introduction

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is the most common treatable autoimmune neuropathy[1] It is typically characterized by progressive proximal and distal paresis as well as sensory deficits, which correspond to severe demyelination and secondary axonal loss of peripheral nerves (reviewed by[2]). Activated T cells can bind to the adhesion molecules and cross the blood-nerve-barrier and contribute to its breakdown Amongst those highly pathogenic T cells are TH17 cells, which were found to be elevated in serum and cerebrospinal fluid samples of patients with active CIDP12. Corresponding to this finding, it was shown that TH17 cells are the determining factor of disease severity, but not target specificity, in a transgenic ICAM-1 deficient mouse model of CIDP13. We were interested to see whether fingolimod treatment could prevent progression of autoimmune neuropathy as assessed by functional and electrophysiological tests

Methods

Results

Conclusion