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Newer Agents in Systemic Treatment
Published in Vineet Relhan, Vijay Kumar Garg, Sneha Ghunawat, Khushbu Mahajan, Comprehensive Textbook on Vitiligo, 2020
Rachita Dhurat, Shilpi Agarwal
Currently, four important members of the JAK family are known. Janus kinase 1 and Janus kinase 2 are involved in host defense, hematopoiesis, neural development, and growth. Janus kinase 3 and tyrosine kinase 2 have a role in the immune response [32].
Current and future topical treatments for psoriasis
Published in M. Alan Menter, Caitriona Ryan, Psoriasis, 2017
Shivani Nanda, Linda Stein Gold
INCB018424 is a Janus kinase 1/2 (JAK 1/2) inhibitor that is being studied in a topical cream formulation. JAKs are involved in signal transduction and lead to the production of many of the proinflammatory cytokines implicated in psoriasis. In a vehicle-controlled, phase IIb study, INCB018424 cream in three different strengths (0.5%, 1.0%, 1.5%) was applied twice daily for 28 days. A dose–response curve was seen with the best improvement with the 1.5% concentration used twice daily. Mild to moderate local irritation reactions were seen in 20% of patients treated with INCB018424 compared with 28% of patients treated with vehicle.79
Celiac disease
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
The numbers of IE-CTLs and TCRγδ+ cells are increased in celiac disease. By contrast, the frequency of intraepithelial CD4+ T cells is unchanged. In addition to increased frequency, IE-CTLs acquire strong cytolytic properties (see later). When patients adopt a gluten-free diet, the number of IE-CTLs returns to normal within weeks or months, whereas the number of TCRγδ+ IELs remains permanently elevated TCRγδ+ IELs in healthy individuals take on an innate-like phenotype characterized by the unique expression of the activating natural cytotoxicity receptors (NCRs) NKp44/NKp46 and a semi-invariant TCR expressing Vδ1Vγ4 gene segments. The heathy subset is displaced in patients with active celiac disease in favor of newly recruited Vδ1+ IELs that produce IFN-γ in a gluten dependent manner and whose TCRs show evidence of adaptively driven expansions with the emergence of a non-germline encoded TCR motif shared across individuals. Importantly, although a gluten-free diet restores the heathy architecture of the intestine, the healthy subset of TCRγδ+ IELs does not recover, thus leaving the compartment permanently devoid of these unique innate-like cells. Furthermore, the production of IFN-γ by Vδ1+ IELs only when patients eat gluten is compatible with them playing a pathogenic role in celiac disease. The identification of the specificity of expanded TCRγδ+ IELs in celiac disease patients will further increase our understanding of their role in the disease. Finally, while IE-CTL and TCRγδ+ IELs are significantly increased in active celiac disease, the number of IE-ILC is decreased. However, in a subset of celiac disease patients who have developed refractory celiac disease, iCD3+ innate IELs represent more than 20% of total IELs and can comprise more than 90% of IELs in some patients. In refractory celiac disease patients, iCD3+ innate IELs often display mutation in signal transducer and activator of transcription 3 (STAT3) and Janus kinase 1 (JAK1) and can undergo malignant transformation.
Cancer-specific type-I interferon receptor signaling promotes cancer stemness and effector CD8+ T-cell exhaustion
Published in OncoImmunology, 2021
Wang Gong, Christopher R. Donnelly, Blake R. Heath, Emily Bellile, Lorenza A. Donnelly, Hülya F. Taner, Luke Broses, J. Chad Brenner, Steven B. Chinn, Ru-Rong Ji, Haitao Wen, Jacques E. Nör, Jie Wang, Gregory T. Wolf, Yuying Xie, Yu Leo Lei
Although the activation of the IFN-I pathway is essential for myeloid M1-like polarization and cross-priming of T-cells, it is equally important to understand the mechanisms underpinning the discrepancies in these different studies. Unlike the type II and type III interferons, whose production is restricted to a small collection of cell types, IFN-I is highly evolutionarily conserved, and almost all normal cell types express IFN-I induction machinery and its receptor IFNAR1. The activation of a spectrum of pattern recognition receptors, including the Toll-like receptors (TLRs), RNA sensors such as DExD/H-Box Helicase 58 (DDX58, aka Retinoic Acid-inducible Gene I or RIG-I), Interferon Induced with Helicase C Domain 1 (IFIH1, aka Melanoma Differentiation-Associated Protein 5 or MDA5), or DNA sensor cyclic GMP-AMP Synthase (cGAS), leads to the phosphorylation of IRF3 and NF-κB. Nuclear phospho-IRF3 and phospho-p65 form an enhanceosome to drive the generation of IFN-I, which includes 13 subtypes of IFN-α, IFN-β, IFN-ω, IFN-ϵ, and IFN-κ. IFN-I functions in an autocrine or paracrine fashion to engage its receptor constituted by IFNAR1 and IFNAR2 on the plasma membrane. Upon activation, tyrosine kinases Tyrosine Kinase 2 (TYK2) and Janus Kinase 1 (JAK1) are phosphorylated, which leads to the phosphorylation of the Signal Transducers and Activators of Transcription (STAT)1 and STAT2. Within the IFNAR1 transcriptional program, MX Dynamin Like GTPase 1 (MX1) is a transgene that is specifically induced by IFN-I and used as a sensitive surrogate marker for IFNAR1 signaling.
Secukinumab after anti-tumour necrosis factor-α therapy: a phase III study in active rheumatoid arthritis
Published in Scandinavian Journal of Rheumatology, 2018
E Dokoupilová, J Aelion, T Takeuchi, N Malavolta, PP Sfikakis, Y Wang, S Rohrer, HB Richards
Effective biological therapies for rheumatoid arthritis (RA) beyond tumour necrosis factor-α (TNF-α) inhibition remain a drug development priority, as many patients respond poorly to, or are intolerant of, anti-TNF-α therapy (1, 2). Alternative biologicals approved for use in patients for whom anti-TNF-α therapy has failed include those targeting either T or B cells, interleukin-6 (IL-6) (2–6), and, more recently, janus kinase 1 (JAK1)/JAK2 (7). Here, we present results from a multicentre, randomized, placebo-controlled phase III study that assessed the efficacy and safety of the human monoclonal anti-IL-17A antibody secukinumab (8) in a prefilled syringe for subcutaneous (s.c.) self-administration in patients with RA who had an inadequate response to, or intolerance of, anti-TNF-α agents.
Atezolizumab for the treatment of breast cancer
Published in Expert Opinion on Biological Therapy, 2018
Debora Basile, Giacomo Pelizzari, Maria Grazia Vitale, Camilla Lisanti, Marika Cinausero, Donatella Iacono, Fabio Puglisi
Furthermore, not all the patients benefit from this new strategy and cancer cells may acquire resistance mutations repressing the immune system’s reactivation. Specifically, high expression of immunosuppressive genes, mesenchymal transition genes, and immunosuppressive mediators may be associated with innate resistance to immune checkpoint inhibitors. Moreover, acquired resistances can also occur. This may be due to mutations of Janus Kinase-1 (JAK-1), JAK-2, or beta-2-microglobulin. However, these are still preliminary results and further investigations are required to confirm these data.