Development of an IL-17A DNA Vaccine to Treat Systemic Lupus Erythematosus in Mice.

Ikeda Ikeda,Yoshida Yoshida,Morishita Morishita,Koriyama Koriyama,Shimamura Shimamura,Rakugi Rakugi,Nakagami Nakagami

doi:10.3390/vaccines8010083

Ikeda Ikeda, Yoshida Yoshida + Show 5 more

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https://doi.org/10.3390/vaccines8010083

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Journal: Vaccines	Publication Date: Feb 12, 2020
Citations: 4	License type: CC BY 4.0

Affiliation: Osaka University

Abstract

The interleukin-17 (IL-17) family, especially IL-17A, plays an important role in the pathogenesis of systemic lupus erythematosus (SLE). This study developed an IL-17A epitope vaccine to treat SLE in NZBWF1 and MRL/lpr mouse models. A plasmid vector encoding a hepatitis B core (HBc)-IL-17A epitope fusion protein was injected using electroporation into the skeletal muscle of NZBWF1(New Zealand Black mice x New Zealand White mice F1 hybrid strain) or MRL/lpr mice three times at 2-week intervals. As a result, anti-IL-17A antibodies were successfully produced in the HBc-IL-17A group. Accordingly, serum tumor necrosis factor alpha (TNF-α) concentrations were significantly reduced in the HBc-IL-17A group. According to pathological analysis, the IL-17A DNA vaccine significantly suppressed renal tissue damage and macrophage infiltration. Consequently, the survival rate was significantly improved in the HBc-IL-17A group. In addition, we evaluated the antigen reactivity of splenocytes from IL-17A-immunized mice using an enzyme-linked immune absorbent spot (ELISPot) assay for safety evaluation. Splenocytes from IL-17A-immunized mice were significantly stimulated by the HBc epitope peptide, but not by the IL-17A epitope or recombinant IL-17A. These results indicate that the IL-17A vaccine did not induce autoreactive T cells against endogenous IL-17A. This study demonstrates for the first time that an IL-17A DNA vaccine significantly reduced organ damage and extended survival time in lupus-prone mice.

Highlights

Systemic lupus erythematosus (SLE) is a prototypic systemic autoimmune disease characterized by abundant autoreactive CD4+ T cells, excessive autoantibody production, and immune complex deposition, with highly heterogeneous clinical manifestations [1,2]
As anti-IL-17A antibody therapy, we developed a DNA vaccine in this study to induce an anti-IL-17A antibody to treat SLE, since our previous reports successfully documented the development of therapeutic B cell vaccines to neutralize autoantibodies against targets such as angiotensin II [8] and DPP (Dipeptidyl Peptidase)-IV [9]
We predicted the candidate sequence for B cell epitope against mouse IL-17A based on the BepiPred-2.0 system (Department of Health Technology, Lyngby, Denmark; http://www.cbs.dtu.dk/services/BepiPred/)

Summary

Introduction

Systemic lupus erythematosus (SLE) is a prototypic systemic autoimmune disease characterized by abundant autoreactive CD4+ T cells, excessive autoantibody production, and immune complex deposition, with highly heterogeneous clinical manifestations [1,2]. The detailed and specific pathogenesis is not completely understood, several recent reports have indicated that the cytokine interleukin-17A (IL-17A) and its related T helper cell subset, Th17, play critical roles in the pathophysiology of SLE [3,4]. The serum IL-17A concentration in SLE patients has been reported to be significantly higher than that of controls [5,6,7]. Based on these findings, it is hypothesized that type I interferon and IL-17A would form a feedback loop and play an important role in the progression of SLE [4]. As anti-IL-17A antibody therapy, we developed a DNA vaccine in this study to induce an anti-IL-17A antibody to treat SLE, since our previous reports successfully documented the development of therapeutic B cell vaccines to neutralize autoantibodies against targets such as angiotensin II [8] and DPP (Dipeptidyl Peptidase)-IV [9]

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