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

Overview

Journal Mol Ther Methods Clin Dev

Publisher Cell Press

Date 2018 Dec 15

PMID 30547047

Citations 7

Authors

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

Affiliations

Soon will be listed here.

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.

Citing Articles

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