Discovery of BVDU as a promising Drug for autoimmune diseases Therapy by Dendritic-cell-based functional screening

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A detailed strategy for screening new MS drugs

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Multiple sclerosis (MS) is the most widespread, disabling neurodegenerative disease of the brain and spinal cord. The Multiple Sclerosis Foundation estimates that about 2.5 million people around the world have MS. It affects mainly young adults, often diagnosed between the ages of 20 and 40, with rate of progression or relapse that is very difficult to determine. Researchers still do not fully understand all the causes leading to MS. However, autoimmunity and immune dysregulation involving T-cells are now recognized as playing a key role in disease onset and progression. This represents a leading hypothesis for finding new drugs.
In MS, the immune system attacks the protective sheath (myelin) that covers nerve fibers. In this complex biological process, Dendritic-Cells (DC) secrete a set of cytokines that trigger the differentiation of IL-17-expressing T cells. Among these cytokines, IL-6 orchestrates a series of cytokine dependent signaling pathways to further amplify T-cell differentiation, offering an interesting track for screening.
From Dendritic cells amplified and differentiated in-vitro from mouse bone marrow, Shai Chen designed a robust HTS assay (>0.9 as Z’ factor) and identified a potent inhibitor, BVDU, from the LOPAC library. By combining a set of techniques including mRNA quantification, flow-cytometry, Western-blot, and ELISA, the impact of BVDU on DC differentiation, maturation, and cytokine production was assessed. The mechanism of action of this inhibitor on ERK, JNK, p38, and NFΚB signaling pathways is well documented. Last, but not least, potency of the compound on an autoimmune disease mouse model and on primary cultured human DCs are also demonstrated clearly.
From in-vitro models to in-vivo proofs-of-concept, find out how cytokines, notably IL-6, can be quantified to assess compound potencies.
Learn more by reading this article, and become a researcher at the cutting edge of cytokines in autoimmunity disorders.

Abstract

Dendritic cells (DCs) play a critical role in the pathogenesis of autoimmune diseases including multiple sclerosis, and targeting DCs’ cytokines production is an important strategy for autoimmune disease treatment. By establishing a high-throughput screening system, we analyzed the LOPAC drug library to identify drugs that control the secretion of IL-6 by DCs, we selected the most likely candidate drug, BVDU, and found that it affected not only IL-6 production, but also that of IL-12, IL-1β during DC differentiation and maturation. The mechanism studies showed that BVDU treatment restricted the phosphorylation of MAP kinase, which played an important role in DC cytokine production. We further assessed the in vivo therapeutic potentials of BVDU on mouse models including EAE and STZ-induced T1D, and found that BVDU treated EAE mice exhibited significantly lower EAE clinical scores, decreased leukocyte infiltration in central nervous system lesions, and reduced demyelination. As in T1D mice, BVDU treatment also showed promising therapeutic effects based on both alleviated disease symptoms and tissue pathogenesis. More interestingly, the modulating effect of BVDU on IL-6 production was further verified in human primary DCs. The above data supported the promising application of our screen model, and also the potential of BVDU for autoimmune disease therapy.

Details

NATURE Scientific Reports, 2017, Mar 8; 7:43820

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