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The Journal of Allergy and Clinical... Jan 2024Vitiligo is an autoimmune depigmenting disorder with no effective and safe treatments. Its pathogenesis is not fully elucidated. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Vitiligo is an autoimmune depigmenting disorder with no effective and safe treatments. Its pathogenesis is not fully elucidated.
OBJECTIVE
This substudy of a randomized, double-blind, placebo-controlled phase 2b trial (NCT03715829) evaluated effects of ritlecitinib, an oral JAK3/TEC family kinase inhibitor, on skin and blood biomarkers in participants with nonsegmental vitiligo (NSV).
METHODS
Sixty-five adults with NSV participated in the substudy and received daily treatment for 24 weeks with placebo (n = 14) or ritlecitinib with or without a 4-week loading dose: 200 (loading dose)/50 mg (n = 13), 100/50 mg (n = 12), 50 mg (n = 11), 30 mg (n = 8), or 10 mg (n = 6). Skin (lesional and nonlesional) biopsy samples were obtained at baseline and at 4 and 24 weeks. Changes from baseline to weeks 4 and 24 in skin and blood molecular and cellular biomarkers were evaluated by RNA sequencing, quantitative real-time PCR, proteomic analysis, and flow cytometry.
RESULTS
Ritlecitinib-treated groups showed downregulation of immune biomarkers and upregulation of melanocyte-related markers at weeks 4 and 24 compared to baseline and/or placebo. Significant reductions were seen in CD3/CD8 T-cell infiltrates, with significant increases in melanocyte markers (tyrosinase; Melan-A) in NSV lesions in the 50 mg ritlecitinib groups (both P < .05). There was significant, dose-dependent downregulation in T-cell activation, NK, cytotoxic, and regulatory markers in lesional skin (IL-2, IL2-RA, IL-15, CCR7, CD5, CRTAM, NCR1, XCL1, KIR3DL1, FASLG, KLRD; P < .05). T1 and T2 markers were also downregulated in lesional skin and blood in a dose-dependent manner (P < .05). Changes in immune biomarkers correlated with clinical response.
CONCLUSIONS
Ritlecitinib significantly downregulated proinflammatory biomarkers and increased melanocyte products in skin and blood of participants with NSV, suggesting its potential in treatment. Ritlecitinib-mediated changes positively correlated with clinical response.
Topics: Adult; Humans; Vitiligo; Proteomics; Melanocytes; Skin; Biomarkers; Janus Kinase 3
PubMed: 37777018
DOI: 10.1016/j.jaci.2023.09.021 -
Clinical and Experimental Dermatology Sep 2023Janus kinase (JAK) refers to a family of tyrosine kinases that are involved in the production of proinflammatory mediators in response to various extracellular signals.... (Review)
Review
Janus kinase (JAK) refers to a family of tyrosine kinases that are involved in the production of proinflammatory mediators in response to various extracellular signals. The JAK-signal transducer and activator of transcription (STAT) pathway is an appealing target in many inflammatory illnesses as this pathway modulates immune cell activation and T-cell-mediated inflammation in response to several cytokines. The practical considerations of prescription for topical and oral JAK inhibitors (JAKis) in atopic dermatitis, vitiligo and psoriasis have been covered in prior publications. Currently, the US Food and Drug Administration has approved the topical JAKi ruxolitinib for atopic dermatitis and nonsegmental vitiligo. None of the remaining first- or second-generation topical JAKis have been approved for topical application in any dermatological indications so far. For this review, the PubMed database was searched using 'topical' and 'JAK inhibitor' or 'Janus kinase inhibitor' or the names of individual drug molecules as the keyword in the title with no date limits. The description of topical JAKi usage in dermatology from the literature was evaluated in each abstract. The current review concentrates on emphasizing the rising use of topical JAKis in both approved and off-label dermatological applications for both old and novel conditions.
Topics: Humans; Janus Kinase Inhibitors; Dermatitis, Atopic; Vitiligo; Psoriasis; Janus Kinases
PubMed: 37235767
DOI: 10.1093/ced/llad188 -
Nature Biomedical Engineering Apr 2024The limited availability of cytokines in solid tumours hinders maintenance of the antitumour activity of chimeric antigen receptor (CAR) T cells. Cytokine receptor...
The limited availability of cytokines in solid tumours hinders maintenance of the antitumour activity of chimeric antigen receptor (CAR) T cells. Cytokine receptor signalling pathways in CAR T cells can be activated by transgenic expression or injection of cytokines in the tumour, or by engineering the activation of cognate cytokine receptors. However, these strategies are constrained by toxicity arising from the activation of bystander cells, by the suboptimal biodistribution of the cytokines and by downregulation of the cognate receptor. Here we show that replacement of the extracellular domains of heterodimeric cytokine receptors in T cells with two leucine zipper motifs provides optimal Janus kinase/signal transducer and activator of transcription signalling. Such chimeric cytokine receptors, which can be generated for common γ-chain receptors, interleukin-10 and -12 receptors, enabled T cells to survive cytokine starvation without induction of autonomous cell growth, and augmented the effector function of CAR T cells in vitro in the setting of chronic antigen exposure and in human tumour xenografts in mice. As a modular design, leucine zippers can be used to generate constitutively active cytokine receptors in effector immune cells.
Topics: Animals; Humans; Signal Transduction; Receptors, Chimeric Antigen; Mice; Leucine Zippers; STAT Transcription Factors; Janus Kinases; Receptors, Cytokine; T-Lymphocytes; Immunotherapy, Adoptive; Cell Line, Tumor; Xenograft Model Antitumor Assays
PubMed: 38036617
DOI: 10.1038/s41551-023-01143-w -
Antiviral Research Sep 2023Hepatitis E virus (HEV) usually causes a self-limiting disease, but especially immunocompromised individuals are at risk to develop a chronic and severe course of...
Hepatitis E virus (HEV) usually causes a self-limiting disease, but especially immunocompromised individuals are at risk to develop a chronic and severe course of infection. Janus kinase (JAK) inhibitors (JAKi) are a novel drug class for the treatment of autoimmune inflammatory rheumatic disease (AIRD). As JAKs play a key role in innate immunity, viral infections and reactivations are frequently reported during JAKi treatment in AIRD patients. The aim of this study was to characterize the influence of JAKis on HEV replication. To this end, we evaluated liver enzymes of an AIRD patient under JAKi therapy with hepatitis E. Further, experiments with HEV (Kernow-C1 p6) were performed by infection of primary human hepatocytes (PHHs) followed by immunofluorescence staining of viral markers and transcriptomic analysis. Infection experiments in PHHs displayed an up to 50-fold increase of progeny virus production during JAKi treatment and transcriptomic analysis revealed induction of antiviral programs during infection. Upregulation of interferon-stimulated genes (ISG) was perturbed in the presence of JAKis, concomitant with elevated HEV RNA levels. The obtained results suggest that therapeutic JAK inhibition increases HEV replication by modulating the HEV-triggered immune response. Therefore, JAKi treatment and the occurrence of elevated liver enzymes requires a monitoring of potential HEV infections.
Topics: Humans; Hepatitis E; Hepatitis E virus; Janus Kinases; Interferons; Antiviral Agents; Virus Replication
PubMed: 37517633
DOI: 10.1016/j.antiviral.2023.105690 -
Phytomedicine : International Journal... Oct 2023Allergic rhinitis (AR) is a chronic inflammatory disease of the nasal mucosa that is mediated by immunoglobulin E (IgE). Xiao-qing-long-tang (XQLT) is a traditional...
BACKGROUND
Allergic rhinitis (AR) is a chronic inflammatory disease of the nasal mucosa that is mediated by immunoglobulin E (IgE). Xiao-qing-long-tang (XQLT) is a traditional Chinese medicine compound that is widely used to treat respiratory diseases such as AR. However, the underlying mechanism of the effect of XQLT on AR remains unclear.
PURPOSE
To elucidate the effect of XQLT on ovalbumin (OVA)-induced AR and the mechanisms of action.
METHODS
The therapeutic efficacy of XQLT was evaluated in a well-established OVA-induced AR mouse model. Nasal symptoms were analyzed, type 2 cytokines and OVA-sIgE levels were measured, nasal mucosa tissues were collected for histological analysis, and the changes of Group 2 innate lymphoid cells (ILC2s) and the IL-33/ST2 and JAK/STAT signaling pathways in the nasal mucosa were observed.
RESULTS
XQLT significantly alleviated the nasal symptoms and histological damage to the nasal mucosa in AR mice, and reduced the levels of type 2 cytokines and OVA-sIgE. In addition, after XQLT treatment, the numbers of ILC2s in the nasal mucosa of AR mice were reduced, and the mRNA levels of the transcription factors GATA3 and ROR-α were decreased. Moreover, IL-33/ST2 signaling pathway was inhibited. The costimulatory cytokine associated JAK/STAT signaling pathway was also inhibited in ILC2s.
CONCLUSION
Our study demonstrated that XQLT regulated ILC2s through the IL-33/ST2 and JAK/STAT pathways to ameliorate type 2 inflammation in OVA-induced AR. These findings suggest that XQLT might be used to treat AR.
Topics: Animals; Mice; Ovalbumin; Immunity, Innate; Interleukin-1 Receptor-Like 1 Protein; Janus Kinases; Interleukin-33; Lymphocytes; Signal Transduction; STAT Transcription Factors; Rhinitis, Allergic; Cytokines; Disease Models, Animal; Mice, Inbred BALB C
PubMed: 37586158
DOI: 10.1016/j.phymed.2023.155012 -
Expert Review of Clinical Immunology Jun 2024Juvenile dermatomyositis (JDM) is a rare autoimmune disease most commonly with proximal weakness due to inflammation and characteristic skin rashes. Most patients have a... (Review)
Review
INTRODUCTION
Juvenile dermatomyositis (JDM) is a rare autoimmune disease most commonly with proximal weakness due to inflammation and characteristic skin rashes. Most patients have a chronic or polycyclic disease course on standard therapy so better treatments are needed. An interferon signature is well-established in key tissues of JDM. Janus kinase inhibitors (jakinibs), which can decrease IFN signaling, are therefore appealing as a targeted therapy.
AREAS COVERED
Herein is a review of the growing literature on JDM patients in jakinibs, including specifics of their jakinib exposure, summary of efficacy, disease features, and characteristics of patients treated, and safety parameters.
EXPERT OPINION
The vast majority of refractory JDM patients respond to jakinib therapy, though they have varied features, doses, and previous/concurrent medications, and data is largely retrospective. Jakinibs are an exciting and promising treatment in JDM. Evaluation with larger prospective controlled studies is needed to answer remaining questions about jakinibs in JDM regarding dosing, which JDM patients to treat with jakinibs, potential biomarkers to use, and how best to monitor safety risks in JDM.
Topics: Humans; Dermatomyositis; Janus Kinase Inhibitors; Child; Janus Kinases; Interferons; Signal Transduction
PubMed: 38299575
DOI: 10.1080/1744666X.2024.2312819 -
Journal of Hematology & Oncology Jul 2023Myelofibrosis (MF) is a chronic myeloproliferative neoplasm characterized by bone marrow fibrosis, anemia, extramedullary hematopoiesis, and splenomegaly. Patients with... (Review)
Review
Myelofibrosis (MF) is a chronic myeloproliferative neoplasm characterized by bone marrow fibrosis, anemia, extramedullary hematopoiesis, and splenomegaly. Patients with MF are at risk for reduced survival versus the general population and often experience burdensome signs and symptoms that reduce quality of life. The oral Janus kinase (JAK) 1/JAK2 inhibitor ruxolitinib was initially approved by the US Food and Drug Administration in 2011 for the treatment of patients with intermediate or high-risk MF, including primary MF, post-polycythemia vera MF, and post-essential thrombocythemia MF, based on efficacy and safety findings from the randomized, controlled, phase 3 COMFORT trials. Over a decade later, ruxolitinib continues to be the standard of care in higher-risk MF, and dose optimization and management remain crucial for safely maximizing clinical benefits of ruxolitinib. This review summarizes the safety profile of ruxolitinib in patients with MF in the COMFORT trials leading up to approval and in the subsequent JUMP, ROBUST, EXPAND, and REALISE trials; in pooled analyses; and in postmarketing analyses in the 10 years following approval. There is a focus on the occurrence of common hematologic and nonhematologic adverse events, with guidance provided on the management of patients with anemia or thrombocytopenia, including dosing strategies based on findings from the REALISE and EXPAND trials. Finally, to ensure a greater understanding of the safety profile of ruxolitinib, practical considerations are discussed.
Topics: Humans; Primary Myelofibrosis; Quality of Life; Janus Kinase 2; Nitriles; Pyrimidines
PubMed: 37501130
DOI: 10.1186/s13045-023-01471-z -
Inflammopharmacology Oct 2023Curcumin (diferuloylmethane) is a herbal remedy which possesses numerous biological attributes including anti-inflammatory, anti-oxidant and anti-cancer properties.... (Review)
Review
Curcumin (diferuloylmethane) is a herbal remedy which possesses numerous biological attributes including anti-inflammatory, anti-oxidant and anti-cancer properties. Curcumin has been shown to impact a number of signaling pathways including nuclear factor kappa B (NF-KB), reactive oxygen species (ROS), Wingless/Integrated (Wnt), Janus kinase-signal transducer and activator of mitogen-activated protein kinase (MAPK) and transcription (JAK/STAT). P38 belongs to the MAPKs, is known as a stress-activated MAPK and is involved in diverse biological responses. P38 is activated in various signaling cascades. P38 plays a role in inflammation, cell differentiation, proliferation, motility and survival. This cascade can serve as a therapeutic target in many disorders. Extensive evidence confirms that curcumin impacts the P38 MAPK signaling pathway, through which it exerts anti-inflammatory, neuroprotective, and apoptotic effects. Hence, curcumin can positively affect inflammatory disorders and cancers, as well as to increase glucose uptake in cells. This review discusses the pharmacological and therapeutic effects of curcumin as effected through p38 MAPK.
Topics: Curcumin; p38 Mitogen-Activated Protein Kinases; Mitogen-Activated Protein Kinases; Signal Transduction; NF-kappa B; Janus Kinases; MAP Kinase Signaling System
PubMed: 37498375
DOI: 10.1007/s10787-023-01265-2 -
Indian Journal of Dermatology,... 2023For any biological response, transmission of extracellular signals to the nucleus is required for DNA transcription and gene expression. In that respect,... (Review)
Review
For any biological response, transmission of extracellular signals to the nucleus is required for DNA transcription and gene expression. In that respect, cytokines/chemokines are well-known inflammatory agents which play a critical role in signalling pathways by activating the Janus kinase-signal transducers and activators of transcription (JAK-STAT) signalling proteins (Janus kinase-signal transducers and activators of transcription) which are a group of intracellular kinase molecules. Cytokines are a category of small proteins (∼5-25 kDa) that play a major role in cell signalling and are major drivers of an autoimmune response. Here we will discuss the role of Janus kinase-signal transducers and activators of transcription kinase cascades in the inflammatory-proliferative cascades of autoimmune disease and about the recent progress in the development of oral synthetic Janus kinase inhibitors (JAKi) and their therapeutic efficacies in dermatologic and systemic autoimmune diseases. Therapeutic efficacy of Janus kinase inhibitors is now well established in the treatment of array of autoimmune and inflammatory disease: spondylarthritis with a special focus on psoriatic arthritis (PsA) and its dermatologic manifestations (psoriasis) and ankylosing spondylitis (AS), atopic dermatitis (AD), alopecia areata (AA), rheumatoid arthritis (RA) and inflammatory bowel disease (IBD). In addition to the first-generation Janus kinase inhibitors several new-generation Janus kinase inhibitors are currently being evaluated. It is expected that these Janus kinase inhibitors likely have higher potency and less adverse effects as compared to their predecessors. Here we have discussed: (1) the functional significance of the Janus kinase-signal transducers and activators of transcription kinase cascades in the inflammatory-proliferative processes of autoimmune diseases and its cellular/molecular mechanisms and (2) progress in the development of oral synthetic Janus kinase inhibitors and their therapeutic efficacies in several systemic and cutaneous autoimmune diseases.
Topics: Humans; Janus Kinase Inhibitors; Arthritis, Psoriatic; Janus Kinases; Autoimmune Diseases; Cytokines
PubMed: 37609730
DOI: 10.25259/IJDVL_1152_2022 -
Blood Jan 2024Platelet factor 4 (PF4) is an abundant chemokine that is released from platelet α-granules on activation. PF4 is central to the pathophysiology of vaccine-induced...
Platelet factor 4 (PF4) is an abundant chemokine that is released from platelet α-granules on activation. PF4 is central to the pathophysiology of vaccine-induced immune thrombocytopenia and thrombosis (VITT) in which antibodies to PF4 form immune complexes with PF4, which activate platelets and neutrophils through Fc receptors. In this study, we show that PF4 binds and activates the thrombopoietin receptor, cellular myeloproliferative leukemia protein (c-Mpl), on platelets. This leads to the activation of Janus kinase 2 (JAK2) and phosphorylation of signal transducer and activator of transcription (STAT) 3 and STAT5, leading to platelet aggregation. Inhibition of the c-Mpl-JAK2 pathway inhibits platelet aggregation to PF4, VITT sera, and the combination of PF4 and IgG isolated from VITT patient plasma. The results support a model in which PF4-based immune complexes activate platelets through binding of the Fc domain to FcγRIIA and PF4 to c-Mpl.
Topics: Humans; Antigen-Antibody Complex; Blood Platelets; Heparin; Immunologic Factors; Janus Kinase 2; Platelet Factor 4; Receptors, Thrombopoietin; Thrombocytopenia
PubMed: 37883794
DOI: 10.1182/blood.2023020872