Protective Effect of PBCA Nanoparticles Loaded with Thymulin Against the Relapsing-Remitting Form of Experimental Autoimmune Encephalomyelitis in Mice.

Sergey M Lunin,Olga V Glushkova,Tatyana V Novoselova,Svetlana B Parfenyuk,Maxim O Khrenov,Elena G Novoselova

doi:10.3390/ijms20215374

Abstract

Relapsing–remitting experimental autoimmune encephalomyelitis (rEAE) in mice is a model that closely resembles relapsing–remitting multiple sclerosis in humans. This study aims to investigate a new approach to modulation of the inflammatory response in rEAE mice using a thymic peptide thymulin bound to polybutylcyanoacrylate (PBCA) nanoparticles. PBCA nanoparticles were used to prolong the presence of thymulin in the blood. Cytokine levels in blood were measured by ELISA; NF-κB and SAPK/JNK cascade activation, as well as Hsp72 and p53 protein expression, were measured by Western blotting. Animal health statuses were estimated using severity scores. Results showed that the cytokine response in rEAE was multi-staged: an early phase was accompanied by an increase in plasma interferon-γ, while the interleukin (IL)-17 response was markedly increased at a later stage. The stages were attributed to rEAE induction and maintenance phases. Thymulin significantly alleviated symptoms of rEAE and lowered plasma cytokine levels both in early and later stages of rEAE, and decreased NF-κB and SAPK/JNK cascade activation. Thymulin modulated NF-kappaB pathway activity via site-specific phosphorylation of RelA/p65 protein (at Ser276 and Ser536). The effect of nanoparticle-bound thymulin was more pronounced than the effect of free thymulin. Therefore, PBCA–thymulin can be considered a prospective treatment for this pathology.

Highlights

Demyelinating autoimmune diseases are a group of diseases characterised by immune dysfunction that leads to activation of auto-aggressive clones of lymphocytes against myelin host components
Multiple sclerosis is frequently characterised by periodic relapses and remissions, it gradually progresses over time, and at present there are no reported cases of full recovery from the disease
Recently we have shown a regulation of the NF-kappaB pathway in experimental autoimmune encephalomyelitis (EAE) via site-specific phosphorylation of a RelA/p65 protein from the NF-kappaB family

Summary

Introduction

Demyelinating autoimmune diseases are a group of diseases characterised by immune dysfunction that leads to activation of auto-aggressive clones of lymphocytes against myelin host components. These diseases include Devic’s disease, encephalitis periaxialis diffusa, and multiple sclerosis. Immunotherapies are the most promising treatment for multiple sclerosis Such therapies may include, for example, monoclonal antibodies. The complications caused by antibodies are associated with significant immunological adverse reactions These include development of neutralising immunogenicity, secondary immunodeficiency, and secondary autoimmunity. In 2018, daclizumab, an anti-CD25 monoclonal antibody, was withdrawn from the market due to concerns about the development of severe, unpredictable autoimmunity [2] Other approaches, such as corticosteroid administration, have restrictions, related to side-effects or a lack of efficiency. There is currently a need for new therapies that produce no adverse reactions but still effectively decrease the symptoms of demyelinating diseases

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