A Proliferation Inducing Ligand (APRIL) targeted antibody is a safe and effective treatment of murine IgA nephropathy

Myette, James R.; Kano, Toshiki; Suzuki, Hitoshi; Sloan, Susan; Szretter, Kristy J.; Ramakrishnan, B.; Adari, Hedy; Deotale, Ketan; Engler, Frank; Shriver, Zachary; Wollacott, Andrew M.; Suzuki, Yusuke; Pereira, Brian J.G.

doi:10.1016/j.kint.2019.01.031

Cited by 51 publications

(37 citation statements)

References 39 publications

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“…Blockade of APRIL–BCMA signaling by a monoclonal antibody to APRIL was shown to be effective in murine model of systemic lupus erythematosus and immunoglobulin A nephropathy. ( 50 ) Altogether, these findings may indicate the importance of further detailed investigation of the BAFF/APRIL system as a potential therapeutic target for PBC.…”

Section: Discussionmentioning

confidence: 88%

Integrated GWAS and mRNA Microarray Analysis Identified IFNG and CD40L as the Central Upstream Regulators in Primary Biliary Cholangitis

et al. 2020

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Genome-wide association studies (GWASs) in European and East Asian populations have identified more than 40 disease-susceptibility genes in primary biliary cholangitis (PBC). The aim of this study is to computationally identify disease pathways, upstream regulators, and therapeutic targets in PBC through integrated GWAS and messenger RNA (mRNA) microarray analysis. Disease pathways and upstream regulators were analyzed with ingenuity pathway analysis in data set 1 for GWASs (1,920 patients with PBC and 1,770 controls), which included 261 annotated genes derived from 6,760 single-nucleotide polymorphisms (P < 0.00001), and data set 2 for mRNA microarray analysis of liver biopsy specimens (36 patients with PBC and 5 normal controls), which included 1,574 genes with fold change >2 versus controls (P < 0.05). Hierarchical cluster analysis and categorization of cell type-specific genes were performed for data set 2. There were 27 genes, 10 pathways, and 149 upstream regulators that overlapped between data sets 1 and 2. All 10 pathways were immune-related. The most significant common upstream regulators associated with PBC disease susceptibility identified were interferon-gamma (IFNG) and CD40 ligand (CD40L). Hierarchical cluster analysis of data set 2 revealed two distinct groups of patients with PBC by disease activity. The most significant upstream regulators associated with disease activity were IFNG and CD40L. Several molecules expressed in B cells, T cells, Kupffer cells, and natural killer-like cells were identified as potential therapeutic targets in PBC with reference to a recently reported list of cell type-specific gene expression in the liver. Conclusion: Our integrated analysis using GWAS and mRNA microarray data sets predicted that IFNG and CD40L are the central upstream regulators in both disease susceptibility and activity of PBC and identified potential downstream therapeutic targets. (Hepatology Communications 2020;4:724-738). P rimary biliary cholangitis (PBC) is a rare chronic autoimmune cholestatic liver disease that predominantly affects middle-aged females. PBC is characterized by lymphocytic cholangitis and gradual destruction of the small intrahepatic bile ducts, which leads to fibrosis, cirrhosis, and

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Section: Discussionmentioning

confidence: 88%

Integrated GWAS and mRNA Microarray Analysis Identified IFNG and CD40L as the Central Upstream Regulators in Primary Biliary Cholangitis

et al. 2020

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“…Similarly, anti-APRIL antibody treatment in grouped ddy mice, a spontaneous IgAN model, was demonstrated to significantly decrease albuminuria, serum levels of IgA, and deposition of glomerular IgA 149 . Likewise, VIS649, the humanized IgG2κ antibody targeting and neutralizing human APRIL through unique epitope engagement, was also reported to decrease the serum levels of IgA by up to 70% in non-human primates 150 . BION-1301, a first-in-class humanized IgG4 anti-APRIL monoclonal antibody, is currently under investigation in a phase 1 trial among adults with IgAN (NCT03945318).…”

Section: Therapeutic Strategies With An Updated Pathophysiological Pementioning

confidence: 98%

Perspectives on how mucosal immune responses, infections and gut microbiome shape IgA nephropathy and future therapies

He¹,

Zhou²,

Lv³

et al. 2020

Theranostics

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Infections have been considered to play a critical role in the pathogenesis of IgA nephropathy (IgAN) because synpharyngitic hematuria is a common feature in IgAN. However, how infections participate in this process is still debated. More recent studies have also revealed that the alteration of the gut microbiome exerts a profound effect on host immune responses, contributing to the etiology or progression of autoimmunity. Considering IgA as the first line of defense against bacterial and viral antigens, this review evaluates the relationships among intestinal infections, gut microbiome, and IgA for a better understanding of the pathogenesis of IgAN. Moreover, as a prototype of IgA immunity, we provide detailed clarification of IgAN pathogenesis to shed light on other diseases in which IgA plays a role. Finally, we discuss potential therapies focusing on microbes and mucosal immune responses in IgAN.

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“…NCT02808429 and NCT02062684). Likewise, VIS649, a humanized anti-APRIL antibody, was also described to reduce the IgA serum levels in non-human primates [102].…”

Section: Emerging Therapiesmentioning

confidence: 99%

The mucosal immune system and IgA nephropathy

2021

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The precise pathogenesis of immunoglobulin A nephropathy (IgAN) is still not clearly established but emerging evidence confirms a pivotal role for mucosal immunity. This review focuses on the key role of mucosa-associated lymphoid tissue (MALT) in promoting the onset of the disease, underlying the relationship among microbiota, genetic factors, food antigen, infections, and mucosal immune response. Finally, we evaluate potential therapies targeting microbes and mucosa hyperresponsiveness in IgAN patients.

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A Proliferation Inducing Ligand (APRIL) targeted antibody is a safe and effective treatment of murine IgA nephropathy

Cited by 51 publications

References 39 publications

Integrated GWAS and mRNA Microarray Analysis Identified IFNG and CD40L as the Central Upstream Regulators in Primary Biliary Cholangitis

Integrated GWAS and mRNA Microarray Analysis Identified IFNG and CD40L as the Central Upstream Regulators in Primary Biliary Cholangitis

Perspectives on how mucosal immune responses, infections and gut microbiome shape IgA nephropathy and future therapies

The mucosal immune system and IgA nephropathy

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