Cessation of anti-VLA-4 therapy in a focal rat model of multiple sclerosis causes an increase in neuroinflammation

S K Vainio,O Solin,O Eskola,J Tuisku,M Haaparanta-Solin,D C Anthony,A M Dickens,J O Rinne,E Löyttyniemi,L Airas

doi:10.1186/s13550-019-0508-7

Abstract

BackgroundPositron emission tomography (PET) can be used for in vivo evaluation of the pathology associated with multiple sclerosis. We investigated the use of longitudinal PET imaging and the 18-kDa translocator protein (TSPO) binding radioligand [18F]GE-180 to detect changes in a chronic multiple sclerosis-like focal delayed-type hypersensitivity experimental autoimmune encephalomyelitis (fDTH-EAE) rat model during and after anti-VLA-4 monoclonal antibody (mAb) treatment. Thirty days after lesion activation, fDTH-EAE rats were treated with the anti-VLA-4 mAb (n = 4) or a control mAb (n = 4; 5 mg/kg, every third day, subcutaneously) for 31 days. Animals were imaged with [18F]GE-180 on days 30, 44, 65, 86 and 142. Another group of animals (n = 4) was used for visualisation the microglia with Iba-1 at day 44 after a 2-week treatment period.ResultsAfter a 2-week treatment period on day 44, there was a declining trend (p = 0.067) in [18F]GE-180-binding in the anti-VLA-4 mAb-treated animals versus controls. However, cessation of treatment for 4 days after a 31-day treatment period increased [18F]GE-180 binding in animals treated with anti-VLA-4 mAb compared to the control group (p = 0.0003). There was no difference between the groups in TSPO binding by day 142.ConclusionsThese results demonstrated that cessation of anti-VLA-4 mAb treatment for 4 days caused a transient rebound increase in neuroinflammation. This highlights the usefulness of serial TSPO imaging in the fDTH-EAE model to better understand the rebound phenomenon.

Highlights

Positron emission tomography (PET) can be used for in vivo evaluation of the pathology associated with multiple sclerosis
Cessation of anti-very late antigen-4 (VLA-4) treatment causes an increase in neuroinflammation Previous magnetic resonance imaging (MRI) studies have demonstrated that fDTHEAE causes a breakdown in the blood-brain barrier (BBB) on day 14
Two weeks of monoclonal antibody (mAb) treatment between days 30 and 44 had effect on [18F]GE-180 binding in the anti-VLA-4-treated animals compared to the controls, on day 44, there was a trend towards decreased binding in the treated animals (p = 0.067, Fig. 3a)

Summary

Introduction

Positron emission tomography (PET) can be used for in vivo evaluation of the pathology associated with multiple sclerosis. The use of focal delayed-type hypersensitivity EAE (fDTH-EAE), which (2019) 9:38 is induced by stereotactic injection of the antigen to a given location within one hemisphere of the animal brain [9], elicits larger, predictable lesions that can be visualised in the rodent brain by TSPO-based PET imaging. This focal model conserves many of the most prominent hallmarks of MS pathogenesis including the recruitment of monocytes and T cells, axonal and myelin damage and, importantly, microglial activation [9,10,11]. The fDTH-EAE lesions are in brain structures, such as in the striatum, to ensure that there are no overt clinical signs, which are often severe in the disseminated models and which give rise to comorbidities and to death [13]

Methods

Results

Conclusion