Spleen Tyrosine Kinase Inhibition Attenuates Autoantibody Production and Reverses Experimental Autoimmune GN

McAdoo, Stephen P.; Reynolds, John J.; Bhangal, Gurjeet; Smith, Jennifer; McDaid, John; Tanna, Anisha; Jackson, William D.; Masuda, Esteban S.; Cook, H. Terence; Pusey, Charles D.; Tam, Frederick W.K.

doi:10.1681/asn.2013090978

Cited by 47 publications

(51 citation statements)

References 37 publications

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“…Future therapeutic studies, therefore, should perhaps focus on identifying "add-on" treatments that might improve outcomes in severe disease. We have recently shown that treatment with fostamatinib, a spleen tyrosine kinase (SYK) inhibitor, effectively reverses crescent formation in rodent models of anti-GBM disease (98,99) (and that intraglomerular SYK can be detected in patient kidney biopsy samples [100]), so it would be of interest to explore the use of this agent in advanced clinical disease. Another interesting agent that has shown efficacy in experimental models is IdeS (IgG-degrading enzyme of Streptococcus pyogenes), an enzyme that is able to cleave both circulating and membrane-bound Ig (101).…”

Section: Future Directionsmentioning

confidence: 99%

Anti-Glomerular Basement Membrane Disease

McAdoo¹,

Pusey²

2017

CJASN

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314

303

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Anti-glomerular basement membrane (anti-GBM) disease is a rare small vessel vasculitis that affects the capillary beds of the kidneys and lungs. It is an archetypic autoimmune disease, caused by the development of directly pathogenic autoantibodies targeting a well characterized autoantigen expressed in the basement membranes of these organs, although the inciting events that induce the autoimmune response are not fully understood. The recent confirmation of spatial and temporal clustering of cases suggests that environmental factors, including infection, may trigger disease in genetically susceptible individuals. The majority of patients develop widespread glomerular crescent formation, presenting with features of rapidly progressive GN, and 40%-60% will have concurrent alveolar hemorrhage. Treatment aims to rapidly remove pathogenic autoantibody, typically with the use of plasma exchange, along with steroids and cytotoxic therapy to prevent ongoing autoantibody production and tissue inflammation. Retrospective cohort studies suggest that when this combination of treatment is started early, the majority of patients will have good renal outcome, although presentation with oligoanuria, a high proportion of glomerular crescents, or kidney failure requiring dialysis augur badly for renal prognosis. Relapse and recurrent disease after kidney transplantation are both uncommon, although de novo anti-GBM disease after transplantation for Alport syndrome is a recognized phenomenon. Copresentation with other kidney diseases such as ANCAassociated vasculitis and membranous nephropathy seems to occur at a higher frequency than would be expected by chance alone, and in addition atypical presentations of anti-GBM disease are increasingly reported. These observations highlight the need for future work to further delineate the immunopathogenic mechanisms of anti-GBM disease, and how to better refine and improve treatments, particularly for patients presenting with adverse prognostic factors.

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Section: Future Directionsmentioning

confidence: 99%

Anti-Glomerular Basement Membrane Disease

McAdoo¹,

Pusey²

2017

CJASN

Self Cite

314

303

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“…Figure 3 shows the targets of Dasatinib obtained from STITCH. In addition to single drug repositioning, synergistic drug combinations can also be repositioned computationally using the network-based approach, e.g., DrugComboRanker and GenSynNET (37, 38), as well as other approaches, e.g., Combinatorial Drug Assembler (CDA) (42,43), DrugPairSeeker (DPS) (44).…”

Section: ∑ ∑mentioning

confidence: 99%

Computational Approaches and Pharmacogenomics Data Resources for Drug Repositioning

2017

MRAJ

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Large-scale data sets of cancer patients have been being generated due to the significantly reduced cost of sequencing full genome of individual patients using the Next Generation Sequencing (NGS) technology. Comprehensive genomics data analysis revealed the diverse dysfunctional biomarkers of individual cancer patients, which are believed to be responsible for heterogeneous drug response. Thus precision medicine is becoming popular that aims to find the optimal treatments for individual patients based on their genomics profiling data. However, it is challenging to interpret the complicated and distinct genome mutation and variation patterns, and associate them to optimal treatments. Though a set of approaches and data resources have been reported to reposition FDA approved drugs and investigational drugs for specific diseases, novel and sophisticated computational approaches are needed urgently to reposition drugs for cancer subtypes or individual patients. In this study, some widely used computational approaches and pharmacogenomics data resources for repositioning optimal drugs are introduced and discussed, which aims to provide a general overview of the genomic data-driven drug repositioning, and help readers understand the topic conveniently.

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“…Although these models have been developed in various species, the most consistent model is that induced in Wistar-Kyoto (WKY) rats. Immunohistochemistry (IHC) study has demonstrated increased glomerular total Syk (T-Syk) and phosphorylated Syk (P-Syk) expression in EAG [16]. T-Syk includes both phosphorylated (active) and unphosphorylated (inactive) forms of Syk.…”

Section: Pathogenic Role Of Syk In Renal Disease (Table 1)mentioning

confidence: 99%

“…Administration of fostamatinib (R788), an oral prodrug of the selective Syk inhibitor tamatinib (R406), completely prevented the induction of EAG when it was given 1 h before immunization. When given from day 18 to 36 after induction of EAG, fostamatinib led to cessation of autoantibody production, reversal of renal injury, preservation of renal function and complete protection from pulmonary hemorrhage [16]. Additionally, fostamatinib inhibited production of proinflammatory cytokines by nephritic glomeruli ex vivo and cultured bone marrow-derived macrophages in vitro, suggesting additional therapeutic effects related to inhibited Fc receptor signaling within macrophages in diseased glomeruli which were independent of suppression of autoantibody production [16].…”

Section: Pathogenic Role Of Syk In Renal Disease (Table 1)mentioning

confidence: 99%

“…In experimental model of early severe renal allograft rejection (Brown Norway to Lewis rats), IHC study showed that all rats with acute rejection had Syk-positive tubulointerstitial infiltrates [35]. Increased Syk expression was also detected in kidney transplant biopsies from patients with antibody-mediated rejection or T-cell mediated rejection [35].…”

Section: Pathogenic Role Of Syk In Renal Disease (Table 1)mentioning

confidence: 99%

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Spleen Tyrosine Kinase: A Crucial Player and Potential Therapeutic Target in Renal Disease

King-Wing¹,

McAdoo²,

Tam³

2016

Nephron

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Spleen tyrosine kinase (Syk), a 72 kDa cytoplasmic non-receptor protein-tyrosine kinase, plays an important role in signal transduction in a variety of cell types. Ever since its discovery in the early 1990s, there has been accumulating evidence to suggest a pathogenic role of Syk in various allergic disorders, autoimmune diseases and malignancies. Additionally, there is emerging data from both pre-clinical and clinical studies that Syk is implicated in the pathogenesis of proliferative glomerulonephritis (GN), including anti-glomerular basement membrane disease, anti-neutrophil cytoplasmic antibody-associated GN, lupus nephritis and immunoglobulin A nephropathy (IgAN). Moreover, recent animal studies have shed light on the importance of Syk in mediating acute renal allograft rejection, Epstein Barr virus-associated post-transplant lymphoproliferative disease and kidney fibrosis. Fostamatinib, an oral Syk inhibitor, has undergone clinical testing in rheumatoid arthritis, refractory immune thrombocytopenic purpura, leukemia and lymphoma. The recent STOP-IgAN trial showed that the addition of non-selective immunosuppressive therapy to intensive supportive care did not improve clinical outcomes in high-risk IgAN patients. A Syk-targeted approach may be beneficial and is currently being evaluated in a phase II randomized controlled trial. In this review, we will discuss the pathogenic role of Syk and potential use of Syk inhibitor in a variety of renal diseases.

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Spleen Tyrosine Kinase Inhibition Attenuates Autoantibody Production and Reverses Experimental Autoimmune GN

Cited by 47 publications

References 37 publications

Anti-Glomerular Basement Membrane Disease

Anti-Glomerular Basement Membrane Disease

Computational Approaches and Pharmacogenomics Data Resources for Drug Repositioning

Spleen Tyrosine Kinase: A Crucial Player and Potential Therapeutic Target in Renal Disease

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