Targeting Dendritic Cells with Alpha 1 Antitrypsin has Therapeutic Potentials in Lupus

Abstract

Abstract Increasing evidence indicate that dendritic cells (DCs) play a critical role in the development and pathogenesis of systemic lupus erythematosus (SLE). Targeting DCs in lupus may be beneficial, but it has not been yet achieved effectively. Alpha 1 antitrypsin (AAT) is a multifunctional protein with anti-inflammatory activity and immunoregulatory functions. In this study, we tested the effects of AAT on DCs and B cells in vitro and its therapeutic potential in vivo in two spontaneous mouse models of lupus. We demonstrated that AAT treatment significantly inhibited DC maturation, induced from C57BL/6 or B6.Sle1.Sle2.Sle3 lupus-prone mice, (using MHC-II IA, CD80, CD86 and CD40 as markers) and function (IFN-I, IL-1β, TNF-α, and IL-12 secretion) in response to TLR4 and TLR9 stimulation. Interestingly, the inhibitory effect of AAT on DCs inhibited B cell proliferation and antibody production induced in DC – B cell co-cultures. Importantly, in vivo AAT treatment prevented the development of kidney disease in MRL/lpr mice and AAT treatment delivered with an AAV-gene therapy vector extended the life span of NZM2410 mice, with 70% mice that received AAT remaining alive at 72 weeks of age vs. all control animals died by 46 weeks of age. In all studies, AAT treatment significantly reduced lupus-associated autoantibody levels, including anti-dsDNA IgG and anti-nuclear autoantibodies. Considering the well-known safety profile of AAT, our results strongly suggest a therapeutic potential of AAT for the treatment of SLE in humans. This work was supported by grants from University of Florida Research Foundation and Grifols Inc.