Suppression of autoreactive T and B lymphocytes by anti-annexin A1 antibody in a humanized NSG murine model of systemic lupus erythematosus

Abstract

Summary Systemic lupus erythematosus is a chronic inflammatory disease which involves multiple organs. Self‐specific B and T cells play a main role in the pathogenesis of lupus and have been defined as a logical target for selective therapy. The protein annexin A1 (ANX A1) is a modulator of the immune system involving many cell types. An abnormal expression of ANX A1 was found on activated B and T cells during autoimmunity, suggesting its importance as a potential therapeutic target. We hypothesize that it may be possible to down‐regulate the activity of autoreactive T and B cells from lupus patients in a humanized immunodeficient mouse model by treating them with an antibody against ANX A1. When cultured in the presence of anti‐ANX A1, peripheral blood mononuclear cells (PBMC) from lupus patients showed a decreased number of immunoglobulin (Ig)G anti‐dsDNA antibody‐secreting plasma cells, decreased T cell proliferation and expression of activation markers and increased B and T cell apoptosis. We employed a humanized model of SLE by transferring PBMCs from lupus patients to immunodeficient non‐obese diabetic‐severe combined immunodeficient (NOD‐SCID) mice. The humanized animals presented autoantibodies, proteinuria and immunoglobulin deposition in the renal glomeruli. Treatment of these NOD‐SCID mice with an anti‐ANX A1 antibody prevented appearance of anti‐DNA antibodies and proteinuria, while the phosphate‐buffered saline (PBS)‐injected animals had high levels after the transfer. The treatment reduced the levels of autoantibodies to several autoantigens, lupus‐associated cytokines and disease symptoms.

Annexin Animal Models—From Fundamental Principles to Translational Research

“…Likewise, coupling anticancer drugs to a peptide that recognizes AnxA1 on the tumour vasculature surface enabled drug delivery across the blood–brain barrier to suppress growth of brain tumours [ 88 ]. Finally, one report described the utilization of a monoclonal AnxA1 antibody to suppress the autoimmune syndrome associated with an abnormal AnxA1 expression on activated B and T cells in a mouse model of systemic lupus erythematosus (SLE), thus underscoring the need for a balanced expression of this immune modulator [ 89 ].…”

Monoclonal antibody therapy that targets phospholipid‐binding protein delays lupus activity in MRL/lpr mice

“…(*P < .05; **P < .01) in comparison with Isotype antibody-treated controls pristane-induced lupus and human SLE. 21,22 The same lymphocytes isolated from young disease-free MRL/lpr animals expressed very low levels of ANX A1 (data not shown).…”

“…The treatment decreased disease activity, protected kidney morphology and prolonged survival compared with the control groups. 21,22 Either CD3 + /CD4 + , CD3 + /CD8 + or CD19 + MRL/lpr lymphocytes from 14-week-old MRL/ lpr mice exhibited surface expression of ANX A1, which links to the increased ANX A1 levels observed in mice with with 200 ng/mouse of anti-ANX A1 antibody or with isotype control antibody. Serum levels of IL-10 in both groups were measured by sandwich ELISA.…”

“…37 Interestingly, the administration of anti-ANX A1 antibody reduced the levels of these cytokines also in a pristane-induced mouse model of SLE in Balb/c mice as well as in a humanized SLE-NSG mice model. 22,23 IL-4 plays an opposing to IFN-γ role and an increased IFN-γ/IL-4 ratio results in the development of lupus-associated hypergammaglobulinemia, autoantibody production and inhibition of Th1-type cytokine production. MRL/lpr mice exhibit reduced levels of IL-4 and IL-4-deficient mice develop autoantibodies and renal damage.…”

“…The treatment of sick animals with this antibody led to downregulation of IgG anti-dsDNA antibody-secreting plasma cells and of proteinuria, improved kidney histology and prolonged survival compared with the control groups. 21,22 In the present study, we have investigated in vivo the possibility to modulate the autoimmune response in lupus-prone MRL/ lpr mouse model of SLE using an anti-ANX A1 antibody. eBioscience) were used for fluorescence-activated cell sorting (FACS) experiments.…”