Alpha 1 Antitrypsin Gene Therapy Extends the Lifespan of Lupus-Prone Mice

Ahmed Samir Elshikha,Ye Yuan,Yuanqing Lu,Mong-Jen Chen,Georges Abboud,Mohammad Ahsanul Akbar,Henrike Plate,Hedwig Wolney,Tanja Hoffmann,Eleni Tagari,Leilani Zeumer,Laurence Morel,Sihong Song

doi:10.1016/j.omtm.2018.10.007

Abstract

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease characterized by high levels of pathogenic autoantibodies and tissue damage. Multiple studies showed that dendritic cell (DC) activation plays a critical role in SLE pathogenesis. Human alpha 1 antitrypsin (hAAT) is a serine proteinase inhibitor with potent anti-inflammatory and cytoprotective properties. In this study, we first examined the effects of hAAT on the functions of DCs from lupus-prone mice, and we showed that hAAT treatment efficiently inhibited CpG- (TLR9 agonist) induced activation of bone marrow-derived conventional and plasmacytoid DCs as well as the production of pro-inflammatory cytokines. The hAAT treatment also attenuated DC help for B cell proliferation and immunoglobulin M (IgM) production. We next tested the protective effect of hAAT protein and gene therapy using recombinant adeno-associated virus 8 (rAAV8-CB-hAAT) in a spontaneous lupus mouse model, and we showed that both treatments decreased autoantibody levels. Importantly, rAAV8-CB-hAAT did not induce an immune response to its transgene product (hAAT), but it showed more pronounced therapeutic effects in reducing urine protein levels and extending the lifespan of these mice. These results indicate that AAT has therapeutic potential in the treatment of SLE in humans.

Highlights

Systemic lupus erythematosus (SLE) is a life-threatening autoimmune disease for which there is no cure
HAAT Treatment Inhibits dendritic cell (DC) Activation Induced by a TLR9 Agonist We have demonstrated that Human alpha antitrypsin (hAAT) inhibited the maturation and function of bone marrow-derived DCs (BMDCs) obtained from non-autoimmune C57BL/6 mice upon stimulation with lipopolysaccharide (LPS) (TLR 4 agonist) or CpG-ODN 1826 (TLR9 agonist).[25]
IL-12 produced by DCs induces the differentiation of Th1 cells, which are expanded in autoimmune diseases,[45] and targeting IL-12 modulates autoimmune diseases in animal models.[46,47]

Summary

Introduction

Systemic lupus erythematosus (SLE) is a life-threatening autoimmune disease for which there is no cure. Most treatment options are symptomatic and nonspecific, using anti-malarial, corticosteroids, and immunosuppressive drugs, which have severe side effects.[1] there is an unmet need for a safe and effective therapy for SLE. Multiple studies have shown that dendritic cells (DCs) play a vital role in SLE pathogenesis.[2,3,4] DCs are antigen-presenting cells (APCs) that consist of conventional DCs (cDCs) and plasmacytoid DCs (pDCs), both of which are activated by Toll-like receptor (TLR) signaling.[2,5,6] TLR3, 7/8, and 9 are endosomal receptors that recognize viral doublestranded RNA, viral single-stranded RNA, and viral or bacterial DNA containing unmethylated CpG motifs, respectively.[5] Stimulation of these TLRs leads to the production of pro-inflammatory cytokines, such as interleukin-6 (IL-6), IL-12, tumor necrosis factor alpha (TNF-a), IL-1b, and type I interferons (IFN-I). These pro-inflammatory cytokines have pleiotropic effects in promoting SLE.[7,8] Elevated levels of IFN-I correlate with disease activity in lupus patients.[9]

Methods

Results

Conclusion