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

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 diseases treatment. By establishing a high-throughput screening system, we analyzed 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 the DCs 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 diseases therapy.

Personalized immunoglobulin aptamers for detection of multiple myeloma minimal residual disease in serum

“…Because ELONA is a heterogeneous assay in which repeated washes remove potential serum interferences, we tested the ability of the aptamer to detect daratumumab in a homogeneous setting. The HTRF format combines fluorescence resonance energy transfer (FRET) with time-resolved measurements that eliminates short-lived background fluorescence [34][35][36][37] . The HTRF ratio (665/620) measures FRET that occurs when two fluorophores (i.e., donor terbium-cryptate (Tb), and acceptor allophycocyanin (d2)) are in proximity.…”

Neuroprotective Potential of Dendritic Cells and Sirtuins in Multiple Sclerosis

“…Therapies that inhibit DCs maturation toward an immunogenic phenotype include those targeting cytokines production, such as anakinra (recombinant IL-1Ra), tocilizumab [150], MOR103 [151,152], KB003, and BVDU [153], and those targeting the co-stimulating molecules that provide positive signals to T cell activation, such as CTLA 4-Ig. In addition, there are several recombinant chimeric antibodies, such as anti-DEC205-MOG [154] and anti-CD11c-MOG [155], targeting DCs' receptors and delivering pro-tolerogenic antigens to DCs.…”

The Application of High‐Throughput Approaches in Identifying Novel Therapeutic Targets and Agents to Treat Diabetes

“…Enhance the expression of thymic insulin; promote central tolerance [190] IL-6 Decrease IL-6 secretion of dendritic cells; ameliorate autoimmune response [188] a)…”

“…For example, by examining the capacity of small molecules to modulate IL‐6 production in DCs, brivudine, an antiviral drug, was discovered with potential therapeutic effects against streptozotocin (STZ)‐induced T1DM mouse model. [ 188 ] Also, data from GWAS indicated the association between variable number tandem repeat (VNTR) alleles, which are located in the insulin promoter , and the risk of T1DM. A shorter variant of VNTR can reduce the expression of insulin in medullary thymic epithelial cells (mTEC), which may lead to the failure of central tolerance and the increased number of insulin‐reactive T cells in periphery.…”