New Treatments for Systemic Lupus Erythematosus on the Horizon: Targeting Plasmacytoid Dendritic Cells to Inhibit Cytokine Production.

Laura M Davison,Trine N Jorgensen

doi:10.4172/2155-9899.1000534

Laura M Davison, Trine N Jorgensen

Open Access

https://doi.org/10.4172/2155-9899.1000534

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Journal: Journal of clinical & cellular immunology	Publication Date: Jan 1, 2017
Citations: 10	License type: cc-by

Affiliation: Cleveland Clinic

Abstract

Patients with systemic lupus erythematosus (SLE) often have elevated levels of type I interferon (IFN, particularly IFNα), a cytokine that can drive many of the symptoms associated with this autoimmune disorder. Additionally, the presence of autoantibody-secreting plasma cells contributes to the systemic inflammation observed in SLE and IFNα supports the survival of these cells. Current therapies for SLE are limited to broad immunosuppression or B cell-targeting antibody-mediated depletion strategies, which do not eliminate autoantibody-secreting plasma cells. Recent clinical trials testing the efficacy of IFNα neutralization in SLE have delivered disappointing results, with primary endpoints not being met or with minimal improvements, while studies evaluating antibody therapy targeting the type I IFN receptor was more successful and is currently being tested in phase III clinical studies. As many studies have supported the idea that plasmacytoid dendritic cells (pDCs) are the main source of IFNα in SLE, specifically targeting pDCs in SLE represents a new therapeutic option. Murine models suggest pDC ablation effectively ameliorates or reduces lupus-like disease development in spontaneous models of lupus and pre-clinical and phase I clinical trials support the safety of such a therapy in humans. Here we review animal studies and the current status of clinical trials targeting IFNα, type I interferon receptor and pDCs in SLE.

Highlights

Systemic lupus erythematosus (SLE) is an autoimmune disorder with wide-ranging clinical manifestations
Further studies are needed to establish efficacy compared with currently available therapies, these studies suggest that targeting IFNα production by plasmacytoid dendritic cells (pDCs) may be highly effective and more specific leading to fewer adverse events [41,42]
Despite these pre-clinical results, a small, short-term phase II clinical trial testing the effect of anti-interleukin 6 (IL-6) monoclonal antibodies (PF-04236921) in SLE patients did not meet the primary endpoints; several parameters, including levels of anti-dsDNA autoantibodies and disease flares, were reduced in patients treated with a lowdose of antibody [46]

Summary

Introduction

Systemic lupus erythematosus (SLE) is an autoimmune disorder with wide-ranging clinical manifestations. Phase IIb clinical trials tested the effect of anifrolumab in 307 SLE patients. It is clear that IFNα levels drop immediately following initial depletion of pDCs [38], studies reporting on the long-term effects on IFNα production and the type I IFN signature have not been published.

Results

Conclusion