Immunophenotype of a Rat Model of Duchenne's Disease and Demonstration of Improved Muscle Strength After Anti-CD45RC Antibody Treatment.

Laure-Hélène Ouisse,Christèle Gras-Le Guen,Vanessa Chenouard,Karl Rouger,Yann Péréon,Nadège Vimond,Régis Josien,Laurent Tesson,Ignacio Anegon,Corinne Huchet,Thibaut Larcher,Carole Guillonneau,Alexis Chenouard,Séverine Remy,Lucas Brusselle,Aude Lafoux,Cécile Braudeau

doi:10.3389/fimmu.2019.02131

Abstract

Corticosteroids (CS) are standard therapy for the treatment of Duchenne's muscular dystrophy (DMD). Even though they decrease inflammation, they have limited efficacy and are associated with significant side effects. There is therefore the need for new protolerogenic treatments to replace CS. Dystrophin-deficient rats (Dmdmdx) closely resemble the pathological phenotype of DMD patients. We performed the first Immunophenotyping of Dmdmdx rats and showed leukocyte infiltration in skeletal and cardiac muscles, which consisted mostly of macrophages and T cells including CD45RChigh T cells. Muscles of DMD patients also contain elevated CD45RChigh T cells. We treated Dmdmdx rats with an anti-CD45RC MAb used in previous studies to deplete CD45RChigh T cells and induce immune tolerance in models of organ transplantation. Treatment of young Dmdmdx rats with anti-CD45RC MAb corrected skeletal muscle strength and was associated with depletion of CD45RChigh T cells with no side effects. Treatment of young Dmdmdx rats with prednisolone resulted in increase in skeletal muscle strength but also severe growth retardation. In conclusion, anti-CD45RC MAb treatment has potential in the treatment of DMD and might eventually result in reduction or elimination of CS use.

Highlights

Duchenne muscular dystrophy (DMD) is the most common inherited muscle disease
The total number of CD45+ mononuclear leukocytes was similar in the skeletal muscle of littermate wild type (WT) and Dmdmdx rats at 2 weeks of age
A sharp increase was seen at 4 weeks of age in Dmdmdx rats which was maintained until week 8 but decreased at weeks 12 and 14 to values that were still significantly higher than those observed in littermate WT rats (Figures 1A,B)

Summary

Introduction

Duchenne muscular dystrophy (DMD) is the most common inherited muscle disease. It is caused by a mutation in the dystrophin gene with X-chromosomal recessive inheritance and affects 1 in 3,500 males [1]. It has a severe prognosis; life expectancy ranges from the late teens to mid-30s. Muscle impairment is rather mild in mdx mice compared to DMD patients. For this reason, new models of mdx mice with more severe disease have been developed [e.g., D2/mdx model; [2]]; new animal models are still required [3]

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