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Inflammation-driven diseases encompass a wide array of pathological conditions characterised by immune system dysregulation leading to tissue damage and dysfunction. Among the myriad of mediators involved in the regulation of inflammation, histamine has emerged as a key modulatory player. Histamine elicits its actions through four rhodopsin-like G-protein-coupled receptors (GPCRs), named chronologically in order of discovery as histamine H 1 , H 2 , H 3 and H 4 receptors (H 1 - 4 R). The relatively low affinity H 1 R and H 2 R play pivotal roles in mediating allergic inflammation and gastric acid secretion, respectively, whereas the high affinity H 3 R and H 4 R are primarily linked to neurotransmission and immunomodulation, respectively. Importantly, however, besides the H 4 R, both H 1 R and H 2 R are also crucial in driving immune responses, the H 2 R tending to promote yet ill-defined and unexploited suppressive, protective and/or resolving processes. The modulatory action of histamine via its receptors on inflammatory cells is described in detail. The potential therapeutic value of the most recently discovered H 4 R in inflammatory disorders is illustrated via a selection of preclinical models. The clinical trials with antagonists of this receptor are discussed and possible reasons for their lack of success described., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Arginase catalyzes the hydrolysis of L-arginine into L-ornithine and urea. The two existing isoforms Arg1 and Arg2 show different cellular localizations and metabolic functions. Arginase activity is crucial for nitrogen detoxification in the urea cycle, synthesis of polyamines, and control of l-arginine bioavailability and nitric oxide production. Despite significant progress in the understanding of the biochemistry and function of arginases, several open questions remain. Recent studies have revealed that the regulation and function of Arg1 and Arg2 are cell-type-specific, species-specific, and profoundly different in mice and humans. The main differences were found in the distribution and function of Arg1 and Arg2 in immune and erythroid cells. Contrary to what was previously thought, Arg1 activity appears to be only partially related to vascular NO signaling under homeostatic conditions in the vascular wall, but its expression is increased under disease conditions and may be targeted by treatment with arginase inhibitors. Arg2 appears to be mainly a catabolic enzyme involved in the synthesis of L-ornithine, polyamine, and proline but may play a putative role in blood pressure control, at least in mice. The immunosuppressive role of arginase-mediated arginine depletion is a promising target for cancer treatment. This review critically revises and discusses the biochemistry, pharmacology, and in vivo function of arginase, focusing on the insights gained from the analysis of cell-specific Arg1 and Arg2 knockout mice and human studies using arginase inhibitors or pegylated recombinant arginase. Significance Statement The review emphasizes the need for further research to deepen our understanding of the regulation of Arg1 and Arg 2 in different cell types under consideration of their localization, species-specificity, and multiple biochemical and physiological roles. This could lead to better pharmacological strategies to target arginase activity in liver, cardiovascular, hematological, immune/infection diseases and cancer., (© 2024 The Authors. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited and is not used for commercial purposes.)

Background: Oral manifestations function as precursors to potential systemic pathologies, signaling early indicators of underlying health complications or immunological dysfunctions. Within these dynamics, circulating inflammatory proteins are recognized as critical mediators in immunopharmacology, bridging holistic health, immune response, and oral health., Methods: We employed genetic data from genome-wide association studies to perform comprehensive Mendelian randomization (MR) analyses on 91 circulating inflammatory proteins and 17 oral phenotypes. Six MR algorithms and five auxiliary control measures were utilized to estimate the causal effects. Subsequently, the MR-Bayesian model averaging (MR-BMA) approach was conducted to elucidate the priorities in host-oral communication, followed by network analyses to explore the interactions among phenotypes., Results: After multiple corrections, MR identified five genetically predicted proteins associated with oral phenotypes. Specifically, FGF21 was correlated with Nteeth and DMFS; hGDNF with gingival pain; CCL4 with stomatitis; and S100A12 with denture use. The causal associations remained robust in sensitivity analyses. Nine protein-phenotype clusters were prioritized using MR-BMA. Among these, S100A12, FGF19, FGF21, and CCL4 exhibited extensive correlations with various oral phenotypes., Conclusions: Our study offers novel genetic insights into the causal relationships, prioritizations, and connections between circulating inflammatory proteins and oral phenotypes. These findings comprehensively depict immune-mediated proteomic profiles underlying the host-oral axis, providing significant implications for clinical practice, public health, and immunopharmacology., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Remission failure and relapse numerate as one of the main problems in patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAVs). The need for new agents that provide effective and safe induction accompanied by sustained remission seems to be urgent in clinical care. The efficacy and safety of rituximab (RTX) for AAVs therapy has been reported in various studies. RTX therapy offers several advantages to treating AAVs patients compared to other therapeutic approaches including reduction of Glucocorticoids (GCs) and conventional Immunosuppressive therapy (IST) usage during both the induction of remission and maintenance phases. This reduction can lead to a lower rate of serious complications making RTX therapy a safer option. It seems that RTX may provide improved clinical outcomes in these patients mediated via B-lymphocyte depletion, Proteinase 3-antineutrophilic cytoplasmic antibody (PR3-ANCA), and myeloperoxidase-antineutrophilic cytoplasmic antibody (MPO-ANCA) titers reduction. In this regard, some uncertainties have been reported to validate the association between such depletion and clinical improvement, as suggested by other sources of autoreactive B cells that did not target with RTX. Due to the prolonged B cell depletion, fixed intervals and adjusted dosage of RTX may be required in patients with AAVs. In this narrative review, we aimed to insight better understand regarding the efficacy of RTX for effective induction and sustained remission in patients with AAVs. It seems that discovering new biomarkers predicting relapse in AAVs patients can lead to future targeted therapy., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background and Purpose: Pulpitis is associated with tooth hypersensitivity and results in pulpal damage. Thermosensitive transient receptor potential (TRP) ion channels expressed in the dental pulp may be key transducers of inflammation and nociception. We aimed at investigating the expression and role of thermo-TRPs in primary human dental pulp cells (hDPCs) in normal and inflammatory conditions., Experimental Approach: Inflammatory conditions were induced in hDPC cultures by applying polyinosinic:polycytidylic acid (poly(I:C)). Gene expression and pro-inflammatory cytokine release were measured by RT-qPCR and ELISA. Functions of TRPA1 channels were investigated by monitoring changes in intracellular Ca 2+ concentration. Mitochondrial superoxide production was measured using a fluorescent substrate. Cellular viability was assessed by measuring the activity of mitochondrial dehydrogenases and cytoplasmic esterases. TRPA1 activity was modified by agonists, antagonists, and gene silencing., Key Results: Transcripts of TRPV1, TRPV2, TRPV4, TRPC5, and TRPA1 were highly expressed in control hDPCs, whereas TRPV3, TRPM2, and TRPM3 expressions were much lower, and TRPM8 was not detected. Poly(I:C) markedly up-regulated TRPA1 but not other thermo-TRPs. TRPA1 agonist-induced Ca 2+ signals were highly potentiated in inflammatory conditions. Poly(I:C)-treated cells displayed increased Ca 2+ responses to H 2 O 2 , which was abolished by TRPA1 antagonists. Inflammatory conditions induced oxidative stress, stimulated mitochondrial superoxide production, resulted in mitochondrial damage, and decreased cellular viability of hDPCs. This inflammatory cellular damage was partly prevented by the co-application of TRPA1 antagonist or TRPA1 silencing., Conclusion and Implications: Pharmacological blockade of TRPA1 channels may be a promising therapeutic approach to alleviate pulpitis and inflammation-associated pulpal damage., (© 2024 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

This article is an autobiographical account of a research career in inflammatory diseases, mechanisms and pharmacotherapy, drug research and development, in academia and industry in various European countries spanning the last 55 years. The author describes how tenacity and independent thought, learned in formative years, and tempered later by the development of good relationships with colleagues have guided his career. This has spanned research, among other fields, on prostaglandins as pro-and anti-inflammatory mediators, oxidative stress and antioxidants, phospholipid mediators, cytokines, innate and adaptive immune responses and the establishment of various inflammatory and immunological models. The author has helped discover and develop novel therapeutic approaches to pain, arthritic, dermatological, respiratory, and autoimmune disorders and contributed to bringing eight drug candidates to clinical trials. He has helped establish new research labs in four different centres and been involved in teaching undergraduate and mature students in three different universities. With extensive experience in scientific publishing and several international awards, he emphasises that without good teamwork, little can be achieved in scientific research., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Apoptosis signal-regulating kinase 1 (ASK1) is an upstream signaling molecule in oxidative stress-induced responses. Because oxidative stress is involved in asthma pathogenesis, ASK1 gene deficiency was investigated in animal models of allergic asthma. However, there is no study to investigate whether ASK1 inhibitors could be applied for asthma to date. Selonsertib, a potent and selective ASK1 inhibitor, was applied to BALB/c mice of an ovalbumin (OVA)-induced allergic asthma model. Selonsertib suppressed antigen-induced degranulation of RBL-2H3 mast cells in a concentration-dependent manner. The administration of selonsertib both before OVA sensitization and OVA challenge significantly reduced airway hyperresponsiveness, and suppressed eosinophil numbers and inflammatory cytokine levels in the bronchoalveolar lavage fluid. Histopathologic examination elucidated less inflammatory responses and reduced mucin-producing cells around the peribronchial regions of the lungs. Selonsertib also suppressed the IgE levels in serum and the protein levels of IL-13 in the bronchoalveolar lavage fluid. These results suggest that selonsertib may ameliorate allergic asthma by suppressing immune responses and be applicable to allergic asthma.

Asthma is characterized by chronic inflammation and respiratory tract remodeling. Peroxisome proliferator-activated receptors (PPARs) play important roles in the pathogenesis and regulation of chronic inflammatory processes in asthma. The role of PPARγ has been studied using synthetic PPARγ agonists in patients with asthma. However, involvement of PPARα/δ has not been studied in asthma. In the present study, we investigated if elafibranor, a PPARα/δ dual agonist, can modulate ovalbumin (OVA)-induced allergic asthma, which is a potential drug candidate for non-alcoholic fatty liver in obese patients. Elafibranor suppresses antigen-induced degranulation in RBL-2H3 mast cells without inducing cytotoxicity in vitro . In mice with OVA-induced allergic asthma, the administration of elafibranor suppressed OVA-induced airway hyper-responsiveness at a dose of 10 mg/kg. Elafibranor also suppressed the OVA-induced increase in immune cells and pro-inflammatory cytokine production in the bronchoalveolar lavage fluid (BALF). Histological studies suggested that elafibranor suppressed OVA-induced lung inflammation and mucin hyper-production in the bronchial airways. In addition, elafibranor suppressed OVA-induced increases in serum immunoglobulin E and IL-13 levels in BALF. Conversely, the present study suggests that elafibranor has the potential for use in patients with allergic asthma.

The effectiveness of natural killer (NK) cells transferred adoptively in combating solid tumours is limited by challenges such as their difficulty in penetrating tumours from the bloodstream and maintaining viability without the support of interleukin-2 (IL-2). Genetically modified NK-92MI cells, which can release IL-2 to sustain their viability, have been identified as a promising alternative. This adaptation addresses the negative consequences of systemic IL-2 administration. The role of PSD-95/discs large/ZO-1 (PDZ)-binding kinase (PBK) in cancer development is recognized, but its effects on immunity are not fully understood. This study explores how PBK expression influences the ability of NK-92MI cells to infiltrate ovarian tumours. Elevated levels of PBK expression have been found in various cancers, including ovarian cancer (OV), with analyses showing higher PBK mRNA levels in tumour tissues compared to normal ones. Immunohistochemistry has confirmed increased PBK expression in OV tissues. Investigations into PBK's role in immune regulation reveal its association with immune cell infiltration, indicating a potentially compromised immune environment in OV with high PBK expression. The small-molecule inhibitor HI-TOPK-032, which inhibits PBK, enhances the cytotoxicity of NK-92MI cells toward OV cells. It increases the production of interferon-γ and tumour necrosis factor-α, reduces apoptosis and encourages cell proliferation. Mechanistic studies showed that contact with OV cells treated with HI-TOPK-032 upregulates CD107a on NK-92 cells. In vivo studies demonstrated that HI-TOPK-032 improves the antitumour effects of NK-92MI cells in OVCAR3 Luc xenografts, extending survival without significant side effects. Safety assessments in mice confirm HI-TOPK-032's favourable safety profile, highlighting its potential as a viable antitumour therapy. These results suggest that combining NK-92MI cells with HI-TOPK-032 enhances antitumour effectiveness against OV, indicating a promising, safe and effective treatment strategy that warrants further clinical investigation., (© 2024 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society). Published by John Wiley & Sons Ltd.)

p38 MAPK has been implicated in the pathogenesis of rheumatoid arthritis and psoriasis. To assess the therapeutic efficacy of the p38 MAPK inhibitor NJK14047 in the treatment of rheumatoid arthritis and psoriasis, we developed mouse models of collagen-induced rheumatoid arthritis (CIA) and imiquimod-induced psoriasis (IIP). NJK14047 was found to suppress arthritis development and psoriasis symptoms and also suppressed histopathological changes induced by CIA and IIP. Furthermore, we established that CIA and IIP evoked increases in the mRNA expression levels of Th1/Th17 inflammatory cytokines in the joints and skin, which was again suppressed by NJK14047. NJK14047 reversed the enlargement of spleens induced by CIA and IIP as well as increases in the levels of inflammatory cytokine in spleens following induction by CIA and IIP. In human SW982 synovial cells, NJK14047 was found to suppress lipopolysaccharide-induced increases in the mRNA expression of proinflammatory cytokines. NJK14047 inhibition of p38 MAPK suppressed the differentiation of naïve T cells to Th17 and Th1 cells. Our findings in this study provide convincing evidence indicating the therapeutic efficacy of the p38 MAPK inhibitor NJK14047 against CIA and IIP, which we speculate could be associated with the suppression on T-cell differentiation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The exponential rise in the prevalence of allergic diseases since the mid-twentieth century has led to a genuine public health emergency and has also fostered major progress in research on the underlying mechanisms and potential treatments. The management of allergic diseases benefits from the biological revolution, with an array of novel immunomodulatory therapeutic and investigational tools targeting players of allergic inflammation at distinct pathophysiological steps. Prominent examples include therapeutic monoclonal antibodies against cytokines, alarmins, and their receptors, as well as small-molecule modifiers of signal transduction mainly mediated by Janus kinases and Bruton's tyrosine kinases. However, the first-line therapeutic options have yet to switch from symptomatic to disease-modifying interventions. Here we present an overview of available drugs in the context of our current understanding of allergy pathophysiology, identify potential therapeutic targets, and conclude by providing a selection of candidate immunopharmacological molecules under investigation for potential future use in allergic diseases.

Rhizome of Alisma orientale has been used as a traditional medicine for treating kidney diseases in East Asian countries. Its inhibitory effects on hypersensitivity responses have been reported for methanol extracts, with alisol B 23-acetate (AB23Ac) being the most active constituent among six terpenes in inhibiting the direct passive Arthus reaction. However, whether AB23Ac has efficacy against allergic asthma has not been tested to date. The in vivo efficacy of AB23Ac in an ovalbumin (OVA)-induced allergic asthma mouse model was evaluated by administrating AB23Ac before OVA sensitization or OVA challenge in BALB/c mice. AB23Ac suppressed antigen-induced degranulation of RBL-2H3 mast cells in a concentration-dependent manner. The administration of AB23Ac both before OVA sensitization and OVA challenge greatly lowered pulmonary resistance and the increase in immune cell counts and inflammatory responses around the peribronchial and perivascular regions. In addition, the inflammatory cytokine levels of Th1/Th2/Th17 cells in the bronchoalveolar lavage fluid decreased in the AB23Ac-treated groups. AB23Ac reduced the number of PAS-stained cells in the lungs. Furthermore, a computer modeling study indicated that AB23Ac can bind tightly to spleen tyrosine kinase (Syk). These results suggest that AB23Ac may ameliorate allergic asthma by suppressing immune responses in dendritic cells during sensitization and in mast cells during challenge periods.

Background and Objectives: Fragaria nubicola has never been evaluated scientifically for its anti-arthritic potential despite its use in folkloric systems of medicine. The research was conducted to assess the potential of F. nubicola against rheumatoid arthritis. Materials and Methods: The current study provided scientific evidence by evaluating the effects of plants using an in vivo CFA-induced model of arthritic rats and subsequent microscopic histopathological evaluation of ankle joints along with the determination of paw edema using a digital water displacement plethysmometer. The study also gave insight by determining levels of pro-inflammatory cytokines, matrix metalloproteinase enzymes (MMPs), prostaglandin E2 (PGE2), nuclear factor kappa B (NF-κB), vascular endothelial growth factor (VEGF), and biochemical and hematological parameters. GCMS analysis was also conducted for the identification of possible anti-inflammatory plant constituents. Results: The data showed that F. nubicola -treated groups attenuated the progression of arthritis and paw edema. Microscopic histopathological evaluation validated the anti-arthritic potential by showing amelioration of bone erosion, infiltration of inflammatory cells, and pannus formation. RT-PCR analysis displayed that treatment with F. nubicola down-regulated IL1β, IL6, TNFα, NF-κB, VEGF, MMP2, MMP3, and MMP9 levels. Moreover, ELISA exhibited a reduction in levels of PGE2 levels in treatment groups. The levels of RBCs, platelets, WBCs, and Hb content were found to be nearly similar to negative control in the treated group. Statistically, a non-significant difference was found when all groups were compared for urea, creatinine, ALT, and AST analysis, indicating the safety of plant extract and fractions at test doses. GCMS analysis of extract and fractions showed the existence of many anti-inflammatory and antioxidant phytochemicals. Conclusion: In conclusion, F. nubicola possessed anti-arthritic properties that might be attributed to the amelioration of MMPs and pro-inflammatory cytokines.

Atezolizumab, a humanized monoclonal antibody against programmed cell death ligand 1 (PD-L1), was initially approved in 2016, around the same time that the sponsor published the minimum serum concentration to maintain the saturation of receptor occupancy (6 μg/mL). The initially approved dose regimen of 1200 mg every 3 weeks (q3w) was subsequently modified to 840 mg q2w or 1680 mg q4w through pharmacokinetic simulations. Yet, each standard regimen yields steady-state trough concentrations (C MIN,SS ) far exceeding (≈ 40-fold) the stated target concentration. Additionally, the steady-state area under the plasma drug concentration-time curve (AUC SS ) at 1200 mg q3w was significantly (P = .027) correlated with the probability of adverse events of special interest (AESIs) in patients with non-small cell lung cancer (NSCLC) and, coupled with excess exposure, this provides incentive to explore alternative dose regimens to lower the exposure burden while maintaining an effective C MIN,SS . In this study, we first identified 840 mg q6w as an extended-interval regimen that could robustly maintain a serum concentration of 6 μg/mL (≥99% of virtual patients simulated, n = 1000), then applied this regimen to an approach that administers 2 "loading doses" of standard-interval regimens for a future clinical trial aiming to personalize dose regimens. Each standard dose was simulated for 2 loading doses, then 840 mg q6w thereafter; all yielded cycle-7 C MIN,SS values of >6 μg/mL in >99% of virtual patients. Further, the AUC SS from 840 mg q6w resulted in a flattening (P = .63) of the exposure-response relationship with adverse events of special interest (AESIs). We next aim to verify this in a clinical trial seeking to validate extended-interval dosing in a personalized approach using therapeutic drug monitoring., (© 2023, The American College of Clinical Pharmacology.)

p38 MAPK has been implicated in the pathogenesis of asthma as well as pro-allergic Th2 cytokines, orosomucoid-like protein isoform 3 (ORMDL3), regulation of sphingolipid biosynthesis, and regulatory T cell-derived IL-35. To elucidate the role of p38 MAPK in the pathogenesis of asthma, we examined the effect of NJK14047, an inhibitor of p38 MAPK, against ovalbumin (OVA)-induced allergic asthma; we administrated NJK14047 before OVA sensitization or challenge in BALB/c mice. As ORMDL3 regulation of sphingolipid biosynthesis has been implicated in childhood asthma, ORMDL3 expression and sphingolipids contents were also analyzed. NJK14047 inhibited antigen-induced degranulation of RBL-2H3 mast cells. NJK14047 administration both before OVA sensitization and challenge strongly inhibited the increase in eosinophil and lymphocyte counts in the bronchoalveolar lavage fluid. In addition, NJK14047 administration inhibited the increase in the levels of Th2 cytokines. Moreover, NJK14047 reduced the inflammatory score and the number of periodic acid-Schiff-stained cells in the lungs. Further, OVA-induced increase in the levels of C16:0 and C24:1 ceramides was not altered by NJK14047. These results suggest that p38 MAPK plays crucial roles in activation of dendritic and mast cells during sensitization and challenge periods, but not in ORMDL3 and sphingolipid biosynthesis.

Liquiritin is a natural flavone with a variety of pharmacological effects derived from the medicinal food homology plant Glycyrrhiza uralensis Fisc h. As a kind of lethal allergic reactions, pseudo-allergic reactions (PARs) arise from the Mas-related G protein coupled receptor X2 (MRGPRX2)-triggered fast degranulation of mast cells (MCs). In the current work, the anti-pseudo-allergy action and potential mechanisms of liquiritin were explored in vivo and in vitro . Liquiritin suppressed the calcium influx and degranulation elicited by Compound 48/80 (C48/80) in mouse peritoneal mast cells (MPMCs). In mice, liquiritin also inhibited the C48/80-elicited hind paw extravasation, as well as the elevations in TNF-α and histamine levels. Molecular docking combined with detection of HEK293T cells expressing human MRGPRX2 showed that liquiritin was a potential MRGPRX2 antagonist and inhibited PARs through the PI3K/AKT and PLCγ signaling pathways downstream of MRGPRX2. The present work opens a new avenue for the PARs management., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Background and aim : Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a rare multisystem autoimmune disease developed by autoantibody production against human neutrophilic granulocytes, including proteinase-3 (PR3) and myeloperoxidase (MPO). The management of AAV patients is difficult due to the multiorgan involvement, high rate of relapse, and complications of immunosuppressive agents that make it challenging. This study aims to investigate the efficacy and safety of rituximab (RTX) therapy in patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) subtypes. Method : The PubMed/Medline database was searched for any studies related to RTX therapy in ANCA-associated vasculitis (GPA and MPA subtypes), from inception to 1 August 2022, and proceeded in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Results : Our search resulted in 1082 initial records. After the elimination of review papers, irrelevant studies, and non-English records, 223 articles were included, and the data related to the efficacy and safety of RTX therapy were extracted. Several randomized and non-randomized studies showed that RTX is an effective treatment option for patients with AAV. Most of the studies showed the very effective effect of RTX in controlling disease in AAV patients, including pediatrics, adults, and elderlies, although RTX cannot completely prevent relapse. However, maintenance therapy helps delay the disease's relapse and causes sustained remission. Not only the licensed dose (375 mg/m 2 intravenous per week for 4 weeks) could induce disease remission, but studies also showed that a single infusion of RTX could be effective. Although RTX could resolve many rare manifestations in AAV patients, there are few reports showing treatment failure. Additionally, few sudies have reported the unexpeted worsening of the disease after RTX administration. Generally, RTX is relatively safe compared to conventional therapies, but some serious adverse effects, mainly infections, cytopenia, hypogammaglobinemia, malignancy, and hypersensitivity have been reported. Conclusions : RTX is an effective and relatively safe therapeutic option for AAV. Studies on the evaluation of the safety profiles of RTX and the prevention of severe RTX-related side effects in AAV patients are required.

Atopic dermatitis (AD) is a chronic inflammatory skin disorder. Suppression of MAPKs and NF-κB is implicated as a vital mechanism of action of several traditional Chinese medicines for AD therapy. Although overexpression of MAPK mRNA in the skin tissue has been shown in the AD model, the roles of each MAPK in AD pathogenesis have rarely been studied. This study examined the effect of NJK14047, an inhibitor of p38 MAPKs, on AD-like skin lesions induced in BALB/c mice by sensitization and challenges with 1-chloro-2,4-dinitrobenzene (CDNB) on dorsal skin and ears, respectively. After induction of AD, NJK14047 (2.5 mg/kg) or dexamethasone (10 mg/kg) was administrated for 3 weeks via intraperitoneal injection. Following its administration, NJK14047 suppressed CDNB-induced AD-like symptoms such as skin hypertrophy and suppressed mast cell infiltration into the skin lesions. It also reduced CDNB-induced increase in T H 2 cytokine (IL-13) and T H 1 cytokines (interferon-γ and IL-12A) levels but did not decrease serum IgE level. Furthermore, NJK14047 blocked CDNB-induced lymph node enlargement. These results suggest that NJK14047, a p38 MAPK inhibitor, might be an optimal therapeutic option with unique modes of action for AD treatment.

Tissue damage occurs in COVID-19 patients due to nsp3-induced Fas-FasL interaction/TNF-related apoptosis. Presently, possible therapeutic-drug, nigellidine against was screened by bioinformatics studies COVID-19. Atomic-Contact-Energy (ACE) and binding-blocking effects were explored of nigellidine ( Nigella sativa L.) in the active/catalytic sites of viral-protein nsp3 and host inflammatory/apoptotic signaling-molecules Fas/TNF receptors TNFR1/TNFR2. A control binding/inhibition of Oseltamivir to influenza-virus neuraminidase was compared here. In AutoDock, Oseltamivir binding-energy (BE) and inhibition-constant (KI) was -4.12 kcal/mol and 959.02. The ACE values (PatchDock) were -167.02/-127.61/-124.91/-122.17/-54.81/-47.07. The nigellidine BE/KI with nsp3 was -7.61 and 2.66, respectively (ACE values were -221.40/-215.62/-113.28). Nigellidine blocked FAS dimer by binding with a BE value of -7.41 kcal/mol. Its strong affinities to TNFR1 (-6.81) and TNFR2 (-5.1) are demonstrated. Our present data suggest that nigellidine may significantly block the TNF-induced inflammatory/Fas-induced apoptotic death-signaling in comparison with a positive-control drug Oseltamivir. Further studies are necessary before proposing nigellidine as medical drug.

Chagas disease is a potentially fatal infection in 21 endemic Latin America countries for which the effectiveness of reference antiparasitic chemotherapy is limited. Thus, we developed three biopharmaceuticals and evaluated the effectiveness of different immunization strategies (recombinant protein NTPDase-1 [rNTPDase-1], DNA plasmid encoding Trypanosoma cruzi NTPDase-1 [TcNTPDase-1] and DNA-NTPDase-1 prime/rNTPDase-1 boost [Prime-boost]) based on the surface ecto-nucleoside triphosphate diphosphohydrolase (ecto-NTPDase) enzyme of T. cruzi in animals challenged with a virulent strain (Y) of this parasite. BALB/c mice were immunized three times at 30 days intervals, challenged with T. cruzi 15 days after the last immunization, and euthanized 30 days after T. cruzi challenge. Our results showed limited polarization of specific anti-ecto-NTPDase immunoglobulins in mice receiving both immunization protocols. Conversely, the Prime-boost strategy stimulated the Th1 protective phenotype, upregulating TNF-α and downregulating IL-10 production while increasing the activation/distribution of CD3 + /CD8 + , CD4 + /CD44 hi and CD8 + /CD44 hi /CD62L cells in immunized and infected mice. Furthermore, IL-6 and IL10 levels were reduced, while the distribution of CD4 + /CD44 hi and CD3 + /CD8 + cells was increased from rNTPDase-1 and DNA-NTPDase1-based immunization strategies. Animals receiving DNA-NTPDase1 and Prime-boost protocols before T. cruzi challenged exhibited an enhanced immunological response associated with IL-17 upregulation and remarkable downregulation of heart parasitism (T. cruzi DNA) and mortality. These findings indicated that NTPDase-1 with Prime-boost strategy induced a protective and sustained Th17 response, enhancing host resistance against T. cruzi. Thus, ecto-NTPDase is a potentially relevant and applicable in the development of biopharmaceuticals with greater immunoprophylactic potential for Chagas disease., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

We are living in a golden age of medicine in which the availability of prenatal diagnosis, fetal therapy, and gene therapy/editing make it theoretically possible to repair almost any defect in the genetic code. Furthermore, the ability to diagnose genetic disorders before birth and the presence of established surgical techniques enable these therapies to be delivered safely to the fetus. Prenatal therapies are generally used in the second or early third trimester for severe, life-threatening disorders for which there is a clear rationale for intervening before birth. While there has been promising work for prenatal gene therapy in preclinical models, the path to a clinical prenatal gene therapy approach is complex. We recently held a conference with the University of California, San Francisco-Stanford Center of Excellence in Regulatory Science and Innovation, researchers, patient advocates, regulatory (members of the Food and Drug Administration), and other stakeholders to review the scientific background and rationale for prenatal somatic cell gene therapy for severe monogenic diseases and initiate a dialogue toward a safe regulatory path for phase 1 clinical trials. This review represents a summary of the considerations and discussions from these conversations., (© 2022, The American College of Clinical Pharmacology.)

Acute myeloid leukemia (AML) is an aggressive malignancy that requires rapid treatment with chemotherapies to reduce tumor burden. However, these chemotherapies can compromise lymphocyte function, thereby hindering normal anti-tumor immune responses and likely limiting the efficacy of subsequent immunotherapy. To better understand these negative impacts, we assessed the immunological effects of standard-of-care AML therapies on lymphocyte phenotype and function over time. When compared to healthy donors, untreated AML patients showed evidence of lymphocyte activation and exhaustion and had more prevalent CD57 + NKG2C + adaptive NK cells, which was independent of human cytomegalovirus (HCMV) status. HMA/venetoclax treatment resulted in a greater fraction of T cells with effector memory phenotype, inhibited IFN-γ secretion by CD8 + T cells, upregulated perforin expression in NK cells, downregulated PD-1 and 2B4 expression on CD4 + T cells, and stimulated Treg proliferation and CTLA-4 expression. Additionally, we showed increased expression of perforin and CD39 and enhanced IFN-γ production by T cells from pre-treatment blood samples of venetoclax-resistant AML patients. Our results provide insight into the lymphocyte status in previously untreated AML patients and the effects of standard-of-care treatments on their biology and functions. We also found novel pre-treatment characteristics of T cells that could potentially predict venetoclax resistance.

Background and Purpose: Transglutaminase type 2 (TG2) catalyses formation of ε-(γ-glutamyl)-lysine bonds between proteins, including those of the extracellular matrix (ECM). Elevated extracellular TG2 leads to accelerated ECM deposition and reduced clearance that underlies tissue scarring and fibrosis. Many transglutaminase inhibitors exist and allowed for proof-of-concept studies in disease models, but their lack of specificity for the TG2 isoform, and/or poor pharmacokinetic/pharmacodynamic properties have limited their clinical application. We sought to develop a high affinity TG2-specific antibody against extracellular TG2 activity, with characteristics suitable for therapeutic development., Experimental Approach: Individual human TG2 domains were used to immunize mice and generate hybridomas. Supernatants were screened for inhibition of recombinant human TG2 activity, with TG2 specificity determined by ELISA., Key Results: Thirteen TG2-specific, hybridoma supernatants inhibited human transamidation activity. Each hybridoma was cloned and the antibody mapped to an epitope in the TG2 core domain, using phage display panning of a TG2 fragment library. Four distinct inhibitory epitopes were determined. The most effective antibodies (AB1, DC1, and BB7) bound to amino acids 313-327 (catalytic core), with an IC 50 of approximately 6-7 nM. The antibodies inhibit TG2 in human cells and block ECM accumulation in a primary human proximal tubular epithelial cell model of fibrosis. Only 7 antibodies inhibited rat TG2, all with higher IC 50 values., Conclusions and Implications: We identified a preferred inhibitory epitope in human TG2, developed antibodies with required characteristics for clinical development, and established that targeted inhibition of extracellular TG2 transamidation activity is sufficient to modify fibrotic remodelling., (© 2021 The British Pharmacological Society.)

Nivolumab and pembrolizumab, anti-programmed cell death protein 1 monoclonal antibodies, have revolutionized oncology but are expensive. Using an interventional pharmacoeconomic approach, these drugs can be administered less often to reduce costs and increase patient convenience while maintaining efficacy. Both drugs are good candidates for less frequent dosing because of long half-lives and no evidence of a relationship of dose to efficacy. Established population pharmacokinetic models for both nivolumab and pembrolizumab were used to simulate profiles for multiple dosing regimens on 1000 randomly generated virtual patients. Simulations were initially performed on standard dose regimens to validate these in silico predictions. Next, simulations of nivolumab 0.3 mg/kg every 3 weeks revealed that >95% of patients maintained ≥1.5 μg/mL at steady state, which was inferred as the minimum effective concentration (MEC) for both drugs. Various alternative dosing regimens were simulated for both drugs to determine which regimen(s) can maintain this MEC in >95% of patients. Extended dosing regimens of nivolumab 240 mg every 4 weeks and 480 mg every 8 weeks along with pembrolizumab 200 mg every 6 weeks were simulated, showing that >95% of patients maintained MEC or greater. These simulations demonstrate the potential to reduce drug exposure by at least 50%, thus substantially reducing patient visits (as well as costs), while maintaining equivalent efficacy. These models provide the scientific justification for an ongoing prospective randomized clinical trial comparing standard interval fixed dosing with extended interval fixed dosing, and ultimately an efficacy-driven comparative trial., (© 2021, The American College of Clinical Pharmacology.)

The COVID-19 pandemic is a highly dramatic concern for mankind. In Italy, the pandemic exerted its major impact throughout the period of February to June 2020. To date, the awkward amount of more than 134,000 deaths has been reported. Yet, post-mortem autopsy was performed on a very modest number of patients who died from COVID-19 infection, leading to a first confirmation of an immune-thrombosis of the lungs as the major COVID-19 pathogenesis, likewise for SARS. Since then (June-August 2020), no targeted early therapy considering this pathogenetic issue was approached. The patients treated with early anti-inflammatory, anti-platelet, anticoagulant and antibiotic therapy confirmed that COVID-19 was an endothelial inflammation with immuno-thrombosis. Patients not treated or scarcely treated with the most proper and appropriate therapy and in the earliest, increased the hospitalization rate in the intensive care units and also mortality, due to immune-thrombosis from the pulmonary capillary district and alveoli. The disease causes widespread endothelial inflammation, which can induce damage to various organs and systems. Therapy must be targeted in this consideration, and in this review, we demonstrate how early anti-inflammatory therapy may treat endothelia inflammation and immune-thrombosis caused by COVID-19, by using drugs we are going to recommend in this paper., (© 2021 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society). Published by John Wiley & Sons Ltd.)

Furazolidone (FZD) is a widely used drug in human and veterinary medicine, and has antibacterial and antiprotozoal action. Although it is widely used as a therapy in various pathological conditions, studies on the efficacy of FZD associated with immune responses are still limited. In this review, we seek to describe which immunopharmacological responses are caused by the administration of FZD. The study followed the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA). A systematic review of clinical trials and in vitro and in vivo experimental studies was carried out, which resulted in 943 papers, of which 35 were considered eligible and, of these 35, 4 were selected for analysis. The studies listed indicated that administration of FZD can modulate pro- or anti-inflammatory pathways, with a probable increase in the expression of reactive oxygen species and a modulation of apoptotic pathways.

Immunosuppression is one of the main mechanisms facilitating tumor expansion. It may be driven by immune checkpoint protein expression, anti-inflammatory cytokine secretion or enhanced metabolic enzyme production, leading to the subsequent build-up of metabolites such as adenosine. Under physiological conditions, adenosine prevents the development of tissue damage resulting from a prolonged immune response; the same mechanism might be employed by tumor tissue to promote immunosuppression. Immune cells expressing A 2A and A 2B adenosine receptors present in an adenosine-rich environment have suppressed effector functions, such as cytotoxicity, proinflammatory cytokine release, antigen presentation and others, making them inert to cancer cells. This study was designed to investigate the dual antagonist potential of SEL330-639 to abolish adenosine-driven immunosuppression. SEL330-639 has slow dissociation kinetics. It inhibits cAMP production in human CD4 + cells, CD8 + cells and moDCs, which leads to diminished CREB phosphorylation and restoration of antitumor cytokine production (IL-2, TNFα, IL-12) in multiple primary human immune cells. The aforementioned results were additionally validated by gene expression analysis and functional assays in which NK cell line cytotoxicity was recovered by SEL330-639. Adenosine-driven immunosuppression is believed to preclude the effectiveness of immune checkpoint inhibitor therapies. Hence, there is an urgent need to develop new immuno-oncological strategies. Here, we comprehensively characterize SEL330-639, a novel dual A 2A /A 2B receptor antagonist effective in both lymphoid and myeloid cell populations with nanomolar potency. Due to its tight binding to the A 2A and A 2B receptors, this binding is sustained even at high adenosine concentrations mimicking the upper limit of the range of adenosine levels observed in the tumor microenvironment., (Copyright © 2021 Elsevier B.V. All rights reserved.)

European Journal of Pharmacology has published a special issue entitled Therapeutic targets and pharmacological treatment of COVID-19 that contains more than 30 manuscripts. Scientists from around the world contributed both review articles and original manuscripts that are remarkable in their diversity. Each contribution offers a unique perspective on the current approaches of the discipline called pharmacology. Yet the contributions share an enthusiasm to put forward a fresh viewpoint and make a positive difference by the exchange of ideas during the troubled times of this pandemic. What other enterprise but science can unite so many diverse cultures and nationalities in global uncertainty and discord, and mobilize an effective response against a common enemy. The efforts of science are in stark contrast to those of populism that has introduced division and a self-serving attitude that are not simply ill-matched to tackle the pandemic, but foster its spread and severity. We trust that the readers of European Journal of Pharmacology will discover new ideas and concepts in our special COVID-19 series as members of the scientific community and shared world., (Copyright © 2020 Elsevier B.V. All rights reserved.)

COVID-19 has caused worldwide death and economic destruction. The pandemic is the result of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has demonstrated high rates of infectivity leading to great morbidity and mortality in vulnerable populations. At present, scientists are exploring various approaches to curb this pandemic and alleviate its health consequences, while racing to develop a vaccine. A particularly insidious aspect of COVID-19 is the delayed overactivation of the body's immune system that is manifested as the cytokine storm. This unbridled production of pro-inflammatory cytokines and chemokines can directly or indirectly cause massive organ damage and failure. Systemic vascular endothelial inflammation and thrombocytopenia are potential consequences as well. In the case of COVID-19, the cytokine storm often fits the pattern of the macrophage activation syndrome with lymphocytopenia. The basis for the imbalance between the innate and adaptive immune systems is not clearly defined, but highlights the effect of SARS-CoV-2 on macrophages. Here we discuss the potential underlying basis for the impact of SARS-CoV-2 on macrophages, both direct and indirect, and potential therapeutic targets. These include granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin 6 (IL-6), interferons, and CXCL10 (IP-10). Various biopharmaceuticals are being repurposed to target the cytokine storm in COVID-19 patients. In addition, we discuss the rationale for activating the macrophage alpha 7 nicotinic receptors as a therapeutic target. A better understanding of the molecular consequences of SARS-CoV-2 infection of macrophages could lead to novel and more effective treatments for COVID-19., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Natural killer (NK) cells are an important arm of the innate immune system. They constitutively express the NKp30 receptor. NKp30-mediated responses are triggered by the binding of specific ligands e.g. tumour cell-derived B7-H6 and involve the secretion of cytotoxic mediators including TNF-α, IFN-γ, perforins and granzymes. The latter two constitute a target cell-directed response that is critical in the process of immunosurveillance. The structure of NKp30 is presented, focusing on the ligand-binding site, on the ligand-induced structural changes and on the experimental data available correlating structure and binding affinity. The translation of NKp30 structural changes to disease progression is also reviewed. NKp30 role in immunotherapy has been explored in chimeric antigen receptor T-cell (CAR-T) therapy. However, antibodies or small ligands targeting NKp30 have not yet been developed. The data reviewed herein unveil the key structural aspects that must be considered for drug design in order to develop novel immunotherapy approaches., (© 2020 The British Pharmacological Society.)

Tabebuia impetiginosa , a plant native to the Amazon rainforest and other parts of Latin America, is traditionally used for treating fever, malaria, bacterial and fungal infections, and skin diseases. Additionally, several categories of phytochemicals and extracts isolated from T. impetiginosa have been studied via various models and displayed pharmacological activities. This review aims to uncover and summarize the research concerning T. impetiginosa , particularly its traditional uses, phytochemistry, and immunopharmacological activity, as well as to provide guidance for future research. A comprehensive search of the published literature was conducted to locate original publications pertaining to T. impetiginosa up to June 2020. The main inquiry used the following keywords in various combinations in titles and abstracts: T. impetiginosa , Taheebo, traditional uses, phytochemistry, immunopharmacological, anti-inflammatory activity. Immunopharmacological activity described in this paper includes its anti-inflammatory, anti-allergic, anti-autoimmune, and anti-cancer properties. Particularly, T. impetiginosa has a strong effect on anti-inflammatory activity. This paper also describes the target pathway underlying how T. impetiginosa inhibits the inflammatory response. The need for further investigation to identify other pharmacological activities as well as the exact target proteins of T. impetiginosa was also highlighted. T. impetiginosa may provide a new strategy for prevention and treatment of many immunological disorders that foster extensive research to identify potential anti-inflammatory and immunomodulatory compounds and fractions as well as to explore the underlying mechanisms of this herb. Further scientific evidence is required for clinical trials on its immunopharmacological effects and safety.

In this article we describe the use of pharmacological and genetic tools coupled with immunoblotting (Western blotting) and targeted mass spectrometry to quantify immune signaling and cell activation mediated by tyrosine kinases. Transfer of the ATP γ phosphate to a protein tyrosine residue activates signaling cascades regulating the differentiation, survival, and effector functions of all cells, with unique roles in immune antigen receptor, polarization, and other signaling pathways. Defining the substrates and scaffolding interactions of tyrosine kinases is critical for revealing and therapeutically manipulating mechanisms of immune regulation. Quantitative analysis of the amplitude and kinetics of these effects is becoming ever more accessible experimentally and increasingly important for predicting complex downstream effects of therapeutics and for building computational models. Secondarily, quantitative analysis is increasingly expected by reviewers and journal editors, and statistical analysis of biological replicates can bolster claims of experimental rigor and reproducibility. Here we outline methods for perturbing tyrosine kinase activity in cells and quantifying protein phosphorylation in lysates and immunoprecipitates. The immunoblotting techniques are a guide to probing the dynamics of protein abundance, protein-protein interactions, and changes in post-translational modification. Immunoprecipitated protein complexes can also be subjected to targeted mass spectrometry to probe novel sites of modification and multiply modified or understudied proteins that cannot be resolved by immunoblotting. Together, these protocols form a framework for identifying the unique contributions of tyrosine kinases to cell activation and elucidating the mechanisms governing immune cell regulation in health and disease. © 2020 The Authors. Basic Protocol 1: Quantifying protein phosphorylation via immunoblotting and near-infrared imaging Alternate Protocol: Visualizing immunoblots using chemiluminescence Basic Protocol 2: Enriching target proteins and isolation of protein complexes by immunoprecipitation Support Protocol: Covalent conjugation of antibodies to functionalized beads Basic Protocol 3: Quantifying proteins and post-translational modifications by targeted mass spectrometry., (© 2020 The Authors.)

Given the critical role that the immune system plays in a multitude of diseases, having a clear understanding of the pharmacology of the immune system is crucial to new drug discovery and development. Here we describe the International Union of Basic and Clinical Pharmacology (IUPHAR) Guide to Immunopharmacology (GtoImmuPdb), which connects expert-curated pharmacology with key immunological concepts and aims to put pharmacological data into the hands of immunologists. In the pursuit of new therapeutics, pharmacological databases are a vital resource to researchers through providing accurate information on the fundamental science underlying drug action. This extension to the existing IUPHAR/British Pharmacological Society Guide to Pharmacology supports research into the development of drugs targeted at modulating immune, inflammatory or infectious components of disease. To provide a deeper context for how the resource can support research we show data in GtoImmuPdb relating to a case study on the targeting of vascular inflammation., (© 2020 The Authors. Immunology published by John Wiley & Sons Ltd.)

Dopamine is well recognized as a neurotransmitter in the brain, and regulates critical functions in a variety of peripheral systems. Growing research has also shown that dopamine acts as an important regulator of immune function. Many immune cells express dopamine receptors and other dopamine related proteins, enabling them to actively respond to dopamine and suggesting that dopaminergic immunoregulation is an important part of proper immune function. A detailed understanding of the physiological concentrations of dopamine in specific regions of the human body, particularly in peripheral systems, is critical to the development of hypotheses and experiments examining the effects of physiologically relevant dopamine concentrations on immune cells. Unfortunately, the dopamine concentrations to which these immune cells would be exposed in different anatomical regions are not clear. To address this issue, this comprehensive review details the current information regarding concentrations of dopamine found in both the central nervous system and in many regions of the periphery. In addition, we discuss the immune cells present in each region, and how these could interact with dopamine in each compartment described. Finally, the review briefly addresses how changes in these dopamine concentrations could influence immune cell dysfunction in several disease states including Parkinson's disease, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, as well as the collection of pathologies, cognitive and motor symptoms associated with HIV infection in the central nervous system, known as NeuroHIV. These data will improve our understanding of the interactions between the dopaminergic and immune systems during both homeostatic function and in disease, clarify the effects of existing dopaminergic drugs and promote the creation of new therapeutic strategies based on manipulating immune function through dopaminergic signaling. Graphical Abstract.

Janus kinase (JAK) inhibitors have emerged as an effective class of therapies for various inflammatory diseases such as rheumatoid arthritis (RA). JAK inhibitors function intracellularly by modulating the catalytic activity of JAKs and disrupting the receptor-mediated signaling of multiple cytokines and growth factors, including those with pro-inflammatory activity. Understanding the inhibition profiles of different JAK inhibitors, based on the associated cytokine receptors and downstream inflammatory pathways affected, is important to identify the potential mechanisms for observed differences in efficacy and safety. This study applied an integrated modeling approach, using in vitro whole blood cytokine inhibition potencies and plasma pharmacokinetics, to determine JAK-dependent cytokine receptor inhibition profiles, in the context of doses estimated to provide a similar clinical response in RA clinical trials. The calculated profiles of cytokine receptor inhibition for the JAK inhibitors tofacitinib, baricitinib, upadacitinib, and filgotinib and its metabolite, were generally similar when clinically efficacious doses for RA were considered. Only minor numerical differences in percentage cytokine receptor inhibition were observed, suggesting limited differentiation of these inhibitors based on JAK pharmacology, with each showing a differential selectivity for JAK1 heterodimer inhibition. Nevertheless, only robust clinical testing involving head-to-head studies will ultimately determine whether there are clinically meaningful differences between these JAK inhibitors. Furthermore, ongoing and future research into inhibitors with alternative JAK selectivity remains of clinical importance. Thus, all JAK inhibitors should be characterized via thorough preclinical, metabolic and pharmacological evaluation, adequate long-term clinical data, and when available, real-world experience., Competing Interests: All authors are employees and shareholders of Pfizer Inc. The authors report that this research did not receive external public or private foundation funding. The study was sponsored by Pfizer Inc., (© 2019 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics.)

Rituximab (RTX) is an approved treatment for rheumatoid arthritis (RA) patients that do not respond adequately to disease-modifying antirheumatic drugs. However, different new concerns, such as efficacy, optimum dose, safety issues, prediction of response to RTX, and pregnancy outcomes have attracted a lot of attention. The PubMed database was systematically reviewed for the last published articles, new findings, and controversial issues regarding RTX therapy in RA using "Rheumatoid arthritis" AND "rituximab" keywords, last updated on June 18, 2019. From 1812 initial recorders, 162 studies met the criteria. Regarding the optimum dose, low-dose RTX therapy (2 × 500 mg) seems as effective as standard dose (2 × 1000 mg), safer, and more cost-effective. The most common reported safety challenges included de novo infections, false negative serologic tests of viral infections, reactivation of chronic infections, interfering with vaccination outcome, and development of de novo psoriasis. Other less reported side effects are infusion reactions, nervous system disorders, and gastrointestinal disorders. Lower exposure to other biologics, presence of some serological markers (e.g., anti-RF, anti-CCP, IL-33, ESR), specific variations in FCGR3A, FCGR2A, TGFβ1, IL6, IRF5, BAFF genes, and also EBV-positivity could be used to predict response to RTX. Although there is no evidence of the teratogenic effect of RTX, it is recommended that women do not expose themselves to RTX at least 6 months before the conception. Only a reversible reduction of B cell-count in the offspring may be the pregnancy-related outcome. Although RTX is an effective therapeutic option for RA, more studies on optimum doses, prevention of RTX-related side effects, prediction of RTX response, and safety during the pregnancy are required.

The immune system responds to acute tissue damage after myocardial infarction (MI) and orchestrates healing and recovery of the heart. However, excessive inflammation may lead to additional tissue damage and fibrosis and exacerbate subsequent functional impairment, leading to heart failure. The appreciation of the immune system as a crucial factor after MI has led to a surge of clinical trials investigating the potential benefits of immunomodulatory agents previously used in hyper-inflammatory conditions, such as autoimmune disease. While the major goal of routine post-MI pharmacotherapy is to support heart function by ensuring appropriate blood pressure and cardiac output to meet the demands of the body, several drug classes also affect a range of immunological pathways and modulate the post-MI immune response, which is crucial to take into account when designing future immunomodulatory trials. This review outlines how routine post-MI pharmacotherapy affects the immune response and may thus influence post-MI outcomes and development towards heart failure. Current key drug classes are discussed, including platelet inhibitors, statins, β-blockers, and renin⁻angiotensin⁻aldosterone inhibitors.

Two pharmacologic approaches that are currently at the forefront of treating advanced cancer are those that center on disrupting critical growth/survival signaling pathways within tumor cells (commonly referred to as "targeted therapies") and those that center on enhancing the capacity of a patient's immune system to mount an antitumor response (immunotherapy). Maximizing responses to both of these approaches requires an understanding of the oncogenic events present in a given patient's tumor and the nature of the tumor-immune microenvironment. Although these 2 modalities were developed and initially used independently, combination regimens are now being tested in clinical trials, underscoring the need to understand how targeted therapies influence immunologic events. Translational studies and preclinical models have demonstrated that targeted therapies can influence immune cell trafficking, the production of and response to chemokines and cytokines, antigen presentation, and other processes relevant to antitumor immunity and immune homeostasis. Moreover, because these and other effects of targeted therapies occur in nonmalignant cells, targeted therapies are being evaluated for use in applications outside of oncology., (© 2017, The American College of Clinical Pharmacology.)

Inflammation is not the only cause of depression and cannot explain its entire pathophysiology, but it is an important pathogenic factor that explains one possible mechanism of depression, with the kynurenine (KYN) pathway of tryptophan at its center. In particular, greater impairment seems to exist in the KYN pathway in inflammation-induced depression related to immunotherapy, autoimmune disease, and infection. In patients with these conditions, immunopharmacology is likely to be an important therapy. To develop this therapy, clear evidence of the immune-KYN pathway must be established via multiple types of experiments. This paper reviews the body of evidence, not only for the action of tryptophan (TRY) and consequent serotonin depletion, but also for the detrimental effects of TRY catabolites and the key enzymes in the KYN pathway that play important roles in the pathophysiology of inflammation-induced depression. In addition, this paper explores a potential treatment strategy for inflammation-induced depression using KYN metabolism., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Antibody-drug conjugates (ADCs) represent an innovative therapeutic approach that provides novel treatment options and hope for patients with cancer. By coupling monoclonal antibodies (mAbs) to cytotoxic small-molecule payloads with a plasma-stable linker, ADCs offer the potential for increased drug specificity and fewer off-target effects than systemic chemotherapy. As evidence for the potential of these therapies, many new ADCs are in various stages of clinical development. Because their structure poses unique challenges to pharmacokinetic and pharmacodynamic characterization, it is critical to recognize the differences between ADCs and conventional chemotherapy in the design of ADC clinical development strategies. Although some properties may be determined mainly by either the mAb or the small-molecule portion, the behavior of these agents is not always predictable. Furthermore, because the absorption, distribution, metabolism, and excretion (ADME) of ADCs are influenced by all 3 of its components (mAb, linker, and payload), it is important to characterize the intact molecule, any target-mediated catabolic clearance of the mAb, and the ADME properties of the small-molecule payload. Here we describe key issues in the clinical development of ADCs, including considerations for designing first-in-human studies for ADCs. We discuss some difficulties of ADC pharmacokinetic characterization and current approaches to overcoming these challenges. Finally, we consider all aspects of clinical pharmacology assessment required during drug development, using examples from the literature to illustrate the discussion., (© 2017, The American College of Clinical Pharmacology.)

Immuno-oncology works through activation of the patient's immune system against cancer, with several advantages over other treatment approaches, including cytotoxic agents and molecular-targeted therapies. The most notable feature of immuno-oncology treatments is the nature of the patient responses achieved, which can be more durable and sustained than with other modalities. Increased understanding of immune system complexity has provided a number of opportunities to advance several strategies for the development of immuno-oncology therapies. This review outlines the clinical pharmacology characteristics and development challenges for the 6 approved immunomodulatory monoclonal antibodies that target 2 immune checkpoint pathways: ipilimumab (an anti-cytotoxic T-lymphocyte antigen-4 antibody) and, more recently, nivolumab and pembrolizumab (both anti-programmed death-1 antibodies) and atezolizumab, avelumab, and durvalumab (all anti-programmed death ligand-1 antibodies). These agents have revealed much about the clinical pharmacology features of immune checkpoint inhibitors as a class, as well as the pharmacometric approaches used to support their clinical development and regulatory approval. The development experiences with these pioneering immuno-oncology agents are likely to serve as useful guides in the discovery, progression, and approval of future drugs or combination of drugs in this class. This review includes summaries of the pharmacokinetics and exposure-response of the immune checkpoint inhibitors approved to date, as well as an overview of some quantitative systems pharmacology approaches. The ability of immuno-oncology to meet its full potential will depend on overcoming development challenges, including the need for clear strategies to determine optimal dose and scheduling for monotherapy as well as combination approaches., (© 2017, The American College of Clinical Pharmacology.)

Searching for new natural drugs that are capable of targeting Th1 and Th17 may lead to development of more effective treatments for inflammatory and autoimmune diseases. Most of the natural drugs can be derived from plants that are used in traditional medicine and folk medicine. The aim of this systematic review is to identify and introduce plants or plant derivatives that are effective on inflammatory diseases by inhibiting Th1 and Th17 responses. To achieve this purpose, the search terms herb, herbal medicine, herbal drug, medicinal plant, phytochemical, traditional Chinese medicine, Ayurvedic medicine, natural compound, inflammation, inflammatory diseases, Th1, Th17, T helper 1 or T helper 17 were used separately in Title/Keywords/Abstract in Web of Science and PubMed databases. In articles investigating the effect of the medicinal plants and their derivatives in inhibiting Th1 and Th17 cells, the effects of eight extracts of the medicinal plants, 21 plant-based compounds and some of their derivatives, and eight drugs derived from the medicinal plants' compounds in inhibiting Th1 and Th17 cells were reviewed. The results showed that medicinal plants and their derivates are able to suppress Th17 and Th1 T cell functions as well as cytokine secretion and differentiation. The results can be used to produce herbal drugs that suppress Th, especially Th17, responses. Copyright © 2017 John Wiley & Sons, Ltd., (Copyright © 2017 John Wiley & Sons, Ltd.)

The spleen tyrosine kinase (SYK) regulates immune cell activation in response to engagement of a variety of receptors, making it an intriguing target for the treatment of inflammatory and autoimmune disorders as well as certain B-cell malignancies. We have previously reported on the discovery and preclinical characterization of PRT062607, a potent and highly selective inhibitor of SYK that exhibits robust anti-inflammatory activity in a variety of animal models. Here we present data from our first human studies aimed at characterizing the pharmacokinetics (PK), pharmacodynamics (PD), and safety of PRT062607 in healthy volunteers following single and multiple oral administrations. PRT062607 demonstrated a favorable PK profile and the ability to completely inhibit SYK activity in multiple whole-blood assays. The PD half-life in the more sensitive assays was approximately 24 hours and returned to predose levels by 72 hours. Selectivity for SYK was observed at all dose levels tested. Analysis of the PK/PD relationship indicated an IC 50 of 324 nM for inhibition of B-cell antigen receptor-mediated B-cell activation and 205 nM for inhibition of FcεRI-mediated basophil degranulation. PRT062607 was safe and well tolerated across the entire range of doses. Clinical PK/PD was related to in vivo anti-inflammatory activity of PRT062607 in the rat collagen-induced arthritis model, which predicts that therapeutic concentrations may be safely achieved in humans for the treatment of autoimmune disease. PRT062607 has a desirable PK profile and is capable of safely, potently, and selectively suppressing SYK kinase function in humans following once-daily oral dosing., (© 2016, The Authors. The Journal of Clinical Pharmacology Published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.)

Multiple sclerosis (MS) is the most common autoimmune disease affecting the central nervous system. It is characterized by auto-reactive T cells that induce demyelination and neuronal degradation. Treatment options are still limited and several MS medications need to be administered by parenteral application but are modestly effective. Oral active drugs such as fingolimod have been weighed down by safety concerns. Consequently, there is a demand for novel, especially orally active therapeutics. Nature offers an abundance of compounds for drug discovery. Recently, the circular plant peptide kalata B1 was shown to silence T-cell proliferation in vitro in an IL-2-dependent mechanism. Owing to this promising effect, we aimed to determine in vivo activity of the cyclotide [T20K]kalata B1 using the MS mouse model experimental autoimmune encephalomyelitis (EAE). Treatment of mice with the cyclotide resulted in a significant delay and diminished symptoms of EAE by oral administration. Cyclotide application substantially impeded disease progression and did not exhibit adverse effects. Inhibition of lymphocyte proliferation and the reduction of proinflammatory cytokines, in particular IL-2, distinguish the cyclotide from other marketed drugs. Considering their stable structural topology and oral activity, cyclotides are candidates as peptide therapeutics for pharmaceutical drug development for treatment of T-cell-mediated disorders.