Sections were directly stained with an FITC conjugated C3 (Nordic Immunology, Susteren, The Netherlands) and FITC conjugated goat anti-mouse IgG (Sigma-Aldrich, San Luis, MO, USA)

Sections were directly stained with an FITC conjugated C3 (Nordic Immunology, Susteren, The Netherlands) and FITC conjugated goat anti-mouse IgG (Sigma-Aldrich, San Luis, MO, USA). and macrophages and immune deposition in both lupus-prone models. Additionally, Hybri treatment produced changes in both inflammatory-related circulating cytokines and kidney gene expression. To summarize, both in vivo studies revealed that the Hybri effect on costimulatory-coinhibitory pathways may effectively mitigate lupus nephritis, with potential for use as a maintenance therapy. Keywords: costimulation, coinhibition, immunomodulation, CTLA4, PDL2, systemic lupus erythematosus, lupus nephritis, glomerulonephritis, autoimmunity, inflammation 1. Introduction Systemic lupus erythematosus (SLE) is a highly complex and chronic autoimmune disease mostly mediated by B-cells, which release multiple circulating autoantibodies such as anti-double-stranded DNA (anti-dsDNA) [1,2]. The immune complexes formed can be deposited in multiple tissues, especially in kidneys, causing inflammation and tissue damage, leading to lupus nephritis (LN) and potentially to chronic renal failure and end-stage kidney disease. There are several murine models used to understand the cellular and genetic components of LN. A classical murine lupus disease develops in NZBWF1 mice, with a phenotype that resembles human lupus disease [3,4]. This strain spontaneously presents lymphadenopathy, splenomegaly, elevated serum anti-dsDNA antibodies and immune complex-mediated glomerulonephritis, leading to kidney failure and animal death [3]. As in human beings, in NZBWF1 mice lupus disease is predominant in females. This lupus disease model has been widely used to study the therapeutic efficacy of several immunosuppressive agents [5,6]. The MRL/lpr mouse strain, with a lymphoproliferative mutation and a defect in apoptosis, suffers from more severe lupus disease with more systemic involvement and nephritis [7]. This strain displays accelerated mortality in both males and females, and has higher concentrations of autoantibodies and immune complexes, including anti-dsDNA [7,8]. Furthermore, MRL/lpr mice specifically develop a full panel of lupus autoantibodies and have additional lupus manifestations such as arthritis, cerebritis, skin rash, and vasculitis [9]. Due to the early onset and Cucurbitacin IIb exacerbated severity of the disease, MRL/lpr mice are also widely used for the assessment of candidate therapies for lupus [10,11]. The pathogenesis of SLE is caused by the appearance of anti-nuclear autoantibodies produced by long-lived plasma cells, which contribute to inflammation that causes cell damage and an increase in antibody titers, resulting in an auto-amplification loop [12,13]. Cucurbitacin IIb This vicious circle is a key factor that can lead to the dysregulated production of aberrant type I interferon (IFN), resulting in a dysregulation of several pathways [14,15]. This ends up producing an activation of plasmacytoid dendritic cells by an increase in the expression of costimulatory molecules, directly activating effector T-cells and finally B-cells through B-cell-activating factor (BAFF) and a proliferation-inducing Cucurbitacin IIb ligand (APRIL) [16,17]. This signaling cascade may affect kidneys by the release of anti-dsDNA autoantibodies by B-cells, which causes the deposition of Rabbit Polyclonal to OR8J3 immune complexes in the renal parenchyma and the activation of the complement system, especially in the glomeruli [18,19]. Standard treatments for SLE were based on nonspecific immunosuppressive agents such as corticosteroids and cyclophosphamide (CYP), and more recently Mycophenolate Mofetil. However, these current treatments may cause several side effects and Cucurbitacin IIb serious infectious complications [20,21]. In recent years, many drugs have been studied for their potential to address different steps in this pathogenic cascade. Many are biological agents directed against specific targets, or costimulatory pathways, aiming to efficiently immunosuppress without the side Cucurbitacin IIb effects caused by conventional immunosuppression drugs. Nifrolumab is currently an approved agent targeting the receptor for IFNa, indicated for SLE. Belimumab is also an approved agent targeting BAFF and indicated for LN. Voclosporine can also arguably be considered an LN-directed therapy due to its effect on T-cells [22,23,24]. Rituximab (anti-CD20), Eculizumab (anti-complement 5), Atacicept (anti-BAFF and anti-APRIL), and Abatacept (anti-CD80) are.