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Summary: Multiple sclerosis (MS) is the leading cause of non‐traumatic neurological disability in the United States in young adults, but current treatments are only partially effective, making it necessary to develop new, innovative therapeutic strategies. Myelin‐specific interleukin (IL)‐17‐producing T helper type 17 (Th17) cells are a major subset of CD4 T effector cells (Teff) that play a critical role in mediating the development and progression of MS and its mouse model, experimental autoimmune encephalomyelitis (EAE), while regulatory T cells (Treg) CD4 T cells are beneficial for suppressing disease. The IL‐6/signal transducer and activator of transcription 3 (STAT‐3) signaling pathway is a key regulator of Th17 and Treg cells by promoting Th17 development and suppressing Treg development. Here we show that three novel small molecule IL‐6 inhibitors, madindoline‐5 (MDL‐5), MDL‐16 and MDL‐101, significantly suppress IL‐17 production in myelin‐specific CD4 T cells in a dose‐dependent manner in vitro. MDL‐101 showed superior potency in suppressing IL‐17 production compared to MDL‐5 and MDL‐16. Treatment of myelin‐specific CD4 T cells with MDL‐101 in vitro reduced their encephalitogenic potential following their subsequent adoptive transfer. Furthermore, MDL‐101 significantly suppressed proliferation and IL‐17 production of anti‐CD3‐activated effector/memory CD45RO+CD4+ human CD4 T cells and promoted human Treg development. Together, these data demonstrate that these novel small molecule IL‐6 inhibitors have the potential to shift the Teff : Treg balance, which may provide a novel therapeutic strategy for ameliorating disease progression in MS. [ABSTRACT FROM AUTHOR]

Purpose of Review: Liver transplantation is a lifesaving therapy for thousands of individuals with end-stage liver disease across the world. Allograft rejection, which is traditionally detected through an invasive graft biopsy, is a major complication for liver transplant recipients in the postoperative period. Biomarkers represent a relatively newer and safer means of detecting and predicting transplant rejection when compared with the current standard of care: liver biopsy. This review serves to compile recent progress in the field of biomarker discovery in liver allograft rejection., Recent Findings: Several promising biomarkers exist in the field of liver transplant rejection. Recent developments include blood genomic assays measuring miRNA, mRNA and donor-derived cell-free DNA. Additionally, serum levels of cytokines, proteoforms, donor-specific antibodies and immunophenotyping have shown promising results in predicting rejection pre and/or posttransplant., Summary: Biomarkers represent a novel method of predicting the risk of developing allograft rejection. The findings discussed in the studies outlined in this review are promising in the potential to improve patient management, reduce complications from over- or under-immunosuppression, and ultimately enhance outcomes., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Multiple sclerosis (MS) is the leading cause of non-traumatic neurological disability in the United States in young adults, but current treatments are only partially effective, making it necessary to develop new, innovative therapeutic strategies. Myelin-specific interleukin (IL)-17-producing T helper type 17 (Th17) cells are a major subset of CD4 T effector cells (T eff ) that play a critical role in mediating the development and progression of MS and its mouse model, experimental autoimmune encephalomyelitis (EAE), while regulatory T cells (T reg ) CD4 T cells are beneficial for suppressing disease. The IL-6/signal transducer and activator of transcription 3 (STAT-3) signaling pathway is a key regulator of Th17 and T reg cells by promoting Th17 development and suppressing T reg development. Here we show that three novel small molecule IL-6 inhibitors, madindoline-5 (MDL-5), MDL-16 and MDL-101, significantly suppress IL-17 production in myelin-specific CD4 T cells in a dose-dependent manner in vitro. MDL-101 showed superior potency in suppressing IL-17 production compared to MDL-5 and MDL-16. Treatment of myelin-specific CD4 T cells with MDL-101 in vitro reduced their encephalitogenic potential following their subsequent adoptive transfer. Furthermore, MDL-101 significantly suppressed proliferation and IL-17 production of anti-CD3-activated effector/memory CD45RO + CD4 + human CD4 T cells and promoted human T reg development. Together, these data demonstrate that these novel small molecule IL-6 inhibitors have the potential to shift the T eff  : T reg balance, which may provide a novel therapeutic strategy for ameliorating disease progression in MS., (© 2019 British Society for Immunology.)