Adalimumab Reduces Photoreceptor Cell Death in A Mouse Model of Retinal Degeneration.

Cristina Martínez-Fernández De La Cámara,José M Millán,Lorena Olivares-González,María Sánchez-Aragó,Regina Rodrigo,David Hervás,Enrique J De La Rosa,Alberto M Hernández-Pinto,José M Cuezva,David Salom,Carmen Cuevas-Martín

doi:10.1038/srep11764

Abstract

Growing evidence suggests that inflammation is involved in the progression of retinitis pigmentosa (RP) both in patients and in animal models. The aim of this study was to investigate the effect of Adalimumab, a monoclonal anti-TNFα antibody, on retinal degeneration in a murine model of human autosomal recessive RP, the rd10 mice at postnatal day (P) 18. In our housing conditions, rd10 retinas were seriously damaged at P18. Adalimumab reduced photoreceptor cell death, as determined by scoring the number of TUNEL-positive cells. In addition, nuclear poly (ADP) ribose (PAR) content, an indirect measure of PAR polymerase (PARP) activity, was also reduced after treatment. The blockade of TNFα ameliorated reactive gliosis, as visualized by decreased GFAP and IBA1 immunolabelling (Müller cell and microglial markers, respectively) and decreased up-regulation of TNFα gene expression. Adalimumab also improved antioxidant response by restoring total antioxidant capacity and superoxide dismutase activity. Finally, we observed that Adalimumab normalized energetic and metabolic pattern in rd10 mouse retinas. Our study suggests that the TNFα blockade could be a successful therapeutic approach to increase photoreceptor survival during the progression of RP. Further studies are needed to characterize its effect along the progression of the disease.

Highlights

Retinitis pigmentosa (RP) is a group of inherited retinal dystrophies characterized by progressive and irreversible loss of vision that in most models studied, parallels photoreceptor cell death[1,2,3]
Sytox Green nuclear staining showed a decline of the number of photoreceptor cell nuclei rows in the outer nuclear layer (ONL) in rd[10] mice
We previously described that Infliximab, other monoclonal anti-TNFα antibody, significantly reduced the number of transferase dUTP nick and labelling (TUNEL)-positive cells in Zaprinast-treated explants of porcine retina[25]

Summary

Introduction

Retinitis pigmentosa (RP) is a group of inherited retinal dystrophies characterized by progressive and irreversible loss of vision that in most models studied, parallels photoreceptor cell death[1,2,3]. Tumor necrosis factor alpha (TNFα ) is a pleiotropic cytokine essential for the induction and maintenance of the inflammatory immune responses It is a well characterized mediator of cellular activities including proliferation, survival, differentiation, inflammation and cell death. Several anti-TNFα agents (Infliximab, Adalimumab, Etarnecept, Golimumab and Certolizumab pegol) have been developed and approved for clinical use in inflammatory diseases such as rheumatoid arthritis, psoriasis and ankylosing spondylitis[18]. To further explore the in vivo potential benefits of blocking TNFα we adopted the rd[10] mouse, a model of human autosomal recessive RP This mouse carries a mutation on the β subunit of the cGMP PDE6 gene (Pde6β) that produces retinal degeneration[2]

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