Immune-mediated Inflammatory Disorders Research Articles

P067 Support Programme for Patients Receiving Imraldi or Benepali Therapy for Immune-Mediated Inflammatory Disorders: 12-Month Persistence

Abstract Background/Aims Low persistence to long-term therapy for chronic disease is a recognised problem. Evidence suggests that increasing patients’ ability to manage their own health condition may positively impact adherence and persistence, leading to improved clinical outcomes. In 2019, Biogen initiated a patient support programme (PSP), in addition to the pre-existing medication home delivery (‘homecare’) service, to improve the knowledge, skills and confidence of patients self-administering Imraldi (adalimumab ADL) and Benepali (etanercept ETN). Methods This real-world, retrospective, database study includes patients enrolled into the PSP within 12 months of ADL/ETN initiation. At first ADL/ETN administration all patients receive a face-to-face nurse training visit, followed by a second nurse training visit or follow-up call to coincide with the second injection. Following this, patients consenting to enrol in the PSP receive nurse coaching calls at Weeks 3, 10, 22 and 34, whilst non-PSP patients self-manage thereafter. The analysis presented here excludes patients who were enrolled into the PSP more than 12 months after ADL/ETN initiation. Data including demographics and type/duration of ADL/ETN therapy was captured by the homecare provider for the PSP cohort from November 2019 to February 2022, and for the non-PSP cohort between February 2016 (ETN) or November 2018 (ADL) and February 2022. Persistence at 12 months post-initiation was estimated using Kaplan-Meier (KM) techniques, overall and by subgroup including indication (rheumatology, dermatology, gastroenterology) and whether biologic naïve or switched from another biologic. Results Persistence at 12 months for patients enrolled in the PSP was 77.5% and in the non-PSP cohort was 73.6%. Lowest persistence by prior biologic exposure was 70.9% in the non-PSP biologic naïve cohort. By therapeutic area, the greatest differential between PSP vs non-PSP group (75.7% vs 67.6%) was in the gastroenterology cohort, which also had the lowest non-PSP persistence of any subgroup. (Table) Conclusion Compared to the non-PSP cohort, patients enrolled in the PSP had higher persistence at 12 months after initiation, across all indications and regardless of prior biologic exposure. This real-world evidence indicates the benefits of a PSP to patients with chronic diseases, and that particular attention should be paid to biologic-naïve patients. Disclosure A. Clark: Corporate appointments; AC is an employee of Biogen Idec Ltd. T. Shering: Corporate appointments; TS is an employee of Biogen Idec Ltd. J. Addison: Corporate appointments; JA is an employee of Biogen Idec Ltd.

Pleural Diseases in Connective Tissue Diseases.

Connective tissue diseases (CTD) are heterogeneous, immune-mediated inflammatory disorders often presenting with multiorgan involvement. With the advent of high-resolution computed tomography, CTD-related pleuritis-pleural thickening and effusion-is now increasingly recognized early in the disease trajectory. The natural history of CTD-related pleural effusions varies from spontaneous resolution to progressive fibrothorax with ventilatory impairment. Treatment of the underlying CTD is necessary to manage the pleural disease. Depending on the degree of symptom burden and physiological insult, specific treatment of pleural disease can include monitoring, repeated aspirations, systemic anti-inflammatory medication, and surgical decortication.

Etrasimod: First Approval.

Etrasimod (VELSIPITY™) is an orally available, small-molecule selective sphingosine-1-phosphate (S1P) receptor modulator being developed by Pfizer for the treatment of ulcerative colitis and other immune-mediated inflammatory disorders. Etrasimod is selective for S1P receptor subtypes S1P1, S1P4 and S1P5 while having minimal activity on S1P3 and no activity on S1P2. Etrasimod received its first approval, in the USA, in October 2023 for the treatment of moderately to severely active ulcerative colitis in adults. Subsequently, the European Medicines Agency adopted a positive opinion in December 2023, recommending the granting of marketing authorisation for etrasimod for the treatment of patients aged ≥ 16years with moderately to severely active ulcerative colitis who have had an inadequate response, lost response, or were intolerant to either conventional therapy, or a biological agent. Etrasimod is also under regulatory review for the treatment of ulcerative colitis in several other countries. Clinical development of etrasimod for use in the treatment of Crohn's disease, atopic dermatitis, eosinophilic oesophagitis and alopecia areata is ongoing worldwide. This article summarises the milestones in the development of etrasimod leading to this first approval for the treatment of ulcerative colitis in adults.

Efficacy and safety of infliximab in the treatment of Kawasaki disease: A systematic review and meta-analysis.

Infliximab is a monoclonal antibody specifically binding tumor necrosis factor-alpha and has been approved for the treatment of several inflammatory disorders. However, the efficacy of infliximab in primary treatment of Kawasaki disease (KD) or retreatment of intravenous immunoglobulin (IVIG)-resistant KD in children is controversial. Therefore, we conducted a meta-analysis to compare the efficacy of infliximab alone or in combination with IVIG to IVIG. Eligible randomized and non-randomized trials were retrieved by searching literature databases prior to May 31, 2023. Pooled odds ratio (OR) and 95% confidence interval (95% CI) were calculated for dichotomous variables, and mean difference (MD) with 95% CI was estimated for continuous variables. A total of 14 eligible studies comprising 1257 participants were included. In refractory KD, infliximab alone was associated with a higher effectiveness rate (OR = 4.48, 95% CI 2.67-7.52) and defervescence rate (OR = 5.01, 95% CI 2.99-8.37) and resulted in a 1.08-day-shorter duration of fever (95% CI 0.61-1.55, P < 0.001) and 1.36-day-shorter length of hospital stay (95% CI 0.65-2.08) compared with IVIG. Incidences of coronary artery lesions (CALs), newly developing CALs, and CAL regression did not differ between both groups. For initial treatment of KD, infliximab in addition to IVIG led to a nominally significant higher effectiveness rate (OR = 2.26, 95% CI 1.02-5.01) and a larger reduction of right coronary artery Z score (MD = -0.24, 95% CI -0.27 to -0.21) but did not show additional efficacy in improving other outcomes. The safety profile was similar between both groups. Conclusion: The meta-analysis demonstrates that infliximab alone is a well-tolerated and effective treatment for IVIG-resistant KD. The additional efficacy of infliximab to IVIG for initial treatment of KD is limited. More large and high-quality trials are needed to confirm the efficacy of infliximab, especially for intensification of primary treatment for KD. What is Known: • Infliximab is a novel monoclonal antibody specifically blocking tumor necrosis factor-alpha and is approved for treatment of several immune-mediated inflammatory disorders. • The efficacy of infliximab in treating children with Kawasaki disease is controversial. What is New: • Infliximab is an effective and safe treatment for children with refractory Kawasaki disease but adds limited efficacy to intravenous immunoglobulin for initial treatment of Kawasaki disease.

Treg in inborn errors of immunity: gaps, knowns and future perspectives.

Regulatory T cells (Treg) are essential for immune balance, preventing overreactive responses and autoimmunity. Although traditionally characterized as CD4+CD25+CD127lowFoxP3hi, recent research has revealed diverse Treg subsets such as Tr1, Tr1-like, and CD8 Treg. Treg dysfunction leads to severe autoimmune diseases and immune-mediated inflammatory disorders. Inborn errors of immunity (IEI) are a group of disorders that affect correct functioning of the immune system. IEI include Tregopathies caused by genetic mutations affecting Treg development or function. In addition, Treg dysfunction is also observed in other IEIs, whose underlying mechanisms are largely unknown, thus requiring further research. This review provides a comprehensive overview and discussion of Treg in IEI focused on: A) advances and controversies in the evaluation of Treg extended subphenotypes and function; B) current knowledge and gaps in Treg disturbances in Tregopathies and other IEI including Treg subpopulation changes, genotype-phenotype correlation, Treg changes with disease activity, and available therapies, and C) the potential of Treg cell-based therapies for IEI with immune dysregulation. The aim is to improve both the diagnostic and the therapeutic approaches to IEI when there is involvement of Treg. We performed a non-systematic targeted literature review with a knowledgeable selection of current, high-quality original and review articles on Treg and IEI available since 2003 (with 58% of the articles within the last 6 years) in the PubMed database.

Applications of cold atmospheric plasma in immune-mediated inflammatory diseases via redox homeostasis: evidence and prospects

As a representative technology in plasma medicine, cold atmospheric plasma (CAP) has beneficial outcomes in surface disinfection, wound repair, tissue regeneration, solid tumor therapy. Impact on immune response and inflammatory conditions was also observed in the process of CAP treatment. Relevant literatures were collected to assess efficacy and summarize possible mechanisms of the innovation. CAP mediates alteration in local immune microenvironment mainly through two ways. One is to down-regulate the expression level of several cytokines, impeding further conduction of immune or inflammatory signals. Intervening the functional phenotype of cells through different degree of oxidative stress is the other approach to manage the immune-mediated inflammatory disorders. A series of preclinical and clinical studies confirmed the therapeutic effect and side effects free of CAP. Moreover, several suggestions proposed in this manuscript might help to find directions for future investigation.

S971 Risk of Major Adverse Cardiovascular Events in Patients With Inflammatory Bowel Diseases or Other Immune-Mediated Inflammatory Disorders on Biologics and Small Molecules: A Systematic Review and Network Meta-Analysis

S971 Risk of Major Adverse Cardiovascular Events in Patients With Inflammatory Bowel Diseases or Other Immune-Mediated Inflammatory Disorders on Biologics and Small Molecules: A Systematic Review and Network Meta-Analysis

Role of serostatus in pediatric neuromyelitis optica spectrum disorders: A nationwide multicentric study.

Neuromyelitis optica spectrum disorders (NMOSD) are immune-mediated inflammatory disorders of the central nervous system (CNS) mostly presenting as optic neuritis and acute myelitis. NMOSD can be associated with seropositivity for aquaporin 4 antibody (AQP4 IgG), myelin oligodendrocyte glycoprotein antibody (MOG IgG), or can be seronegative for both. In this study, we retrospectively examined our seropositive and seronegative pediatric NMOSD patients. Data were collected from all participating centres nationwide. Patients diagnosed with NMOSD were divided into three subgroups according to serology: AQP4 IgG NMOSD, MOG IgG NMOSD, and double seronegative (DN) NMOSD. Patients with at least six months of follow-up were compared statistically. The study included 45 patients, 29 female and 16 male (ratio:1.8), mean age 15.16±4.93 (range 5.5-27) years. Age at onset, clinical manifestations, and cerebrospinal fluid findings were similar between AQP4 IgG NMOSD (n=17), MOG IgG NMOSD (n=10), and DN NMOSD (n=18) groups. A polyphasic course was more frequent in the AQP4 IgG and MOG IgG NMOSD groups than DN NMOSD (p=0.007). The annualized relapse rate and rate of disability were similar between groups. Most common types of disability were related to optic pathway and spinal cord involvement. Rituximab in AQP4 IgG NMOSD, intravenous immunoglobulin in MOG IgG NMOSD, and azathioprine in DN NMOSD were usually preferred for maintenance treatment. In our series with a considerable number of double seronegatives, the three major serological groups of NMOSD were indistinguishable based on clinical and laboratory findings at initial presentation. Their outcome is similar in terms of disability, but seropositive patients should be more closely followed-up for relapses.

Discovery of novel cGAS inhibitors based on natural flavonoids

Cyclic GMP-AMP synthase (cGAS) plays an important role in the inflammatory response. It has been reported that aberrant activation of cGAS is associated with a variety of immune-mediated inflammatory disorders. The development of small molecule inhibitors of cGAS has been considered as a promising therapeutic strategy for the diseases. Flavonoids, a typical class of natural products, are known for their anti-inflammatory activities. Although cGAS is closely associated with inflammation, the potential effects of natural flavonoid compounds on cGAS have been rarely studied. Therefore, we screened an in-house natural flavonoid library by pyrophosphatase (PPiase) coupling assay and identified novel cGAS inhibitors baicalein and baicalin. Subsequently, crystal structures of the two natural flavonoids in complex with human cGAS were determined, which provide mechanistic insight into the anti-inflammatory activities of baicalein and baicalin at the molecular level. After that, a virtual screening based on the crystal structures of baicalein and baicalin in complex with human cGAS was performed. As a result, compound C20 was identified to inhibit both human and mouse cGAS with IC50 values of 2.28 and 1.44 μM, respectively, and its detailed interactions with human cGAS were further revealed by the X-ray crystal structure determination. These results demonstrate the potential of natural products used as hits in drug discovery and provide valuable hints for further development of cGAS inhibitors.

Autoimmune Encephalitis: A Literature Review

Autoimmune encephalitis (AIE) defines brain inflammation caused by a misdirected immune response against self-antigens expressed in the central nervous system. AIE encompasses a group of non-infectious immune-mediated inflammatory disorders of the brain parenchyma often involving the cortical or deep gray matter with or without involvement of the white matter, meninges, or the spinal cord. Suggested mechanisms that may trigger AIE include tumors (paraneoplastic), infections (para-infectious), or it may be cryptogenic. This study represents a review of the common forms of AIE, exploring their causes, diagnostic approaches, and management strategies. The previous and ongoing investigations in this field have been driven by the identification of several pathogenic autoantibodies that cause polysymptomatic neuropsychiatric and neurological diseases. AIE comprises a heterogeneous group of disorders that are at least as common as infectious causes of encephalitis. Early treatment is associated with better prognosis and is crucial for the prevention of severe complications. The underlying mechanisms for activation and autoimmune response in the CNS are still unclear. Further investigations are needed to better explain how immune mechanisms affect nervous system functions.

Dual-Targeted Therapy in Pediatric Inflammatory Bowel Disease: A Comprehensive Review.

Inflammatory bowel disease (IBD) is a chronic systemic immune-mediated disorder. The disease is triggered and perpetuated by a complex interplay between genetic predisposition, dysregulated immune responses, and environmental factors. Pediatric IBD is considered to be more aggressive compared with adult-onset IBD, and commonly requires more intensive pharmacological and surgical treatments. Although the use of targeted therapy, such as biologic therapy and small molecule therapy, is on the rise, there are children with IBD who are refractory to all current therapeutic options. For them, a combination of biologic agents or a biologic agent with small molecules as dual-targeted therapy (DTT) may be a possible therapeutic option. The main indications for DTT are high inflammatory burden and refractoriness to standard therapy, extra-intestinal manifestations of IBD, adverse effects of therapy, and co-existing immune-mediated inflammatory disorders. Several combination therapies were described for pediatric refractory IBD. The main ones were anti-tumor necrosis factor (TNF) agents and vedolizumab (VDZ), anti-TNF and ustekinumab (UST), VDZ and UST, and biologic agents with tofacitinib. DTT exhibits high efficacy, with high rates of clinical response and remission as well as biomarker remission. The data on endoscopic and radiologic remission are scarce. Most of the adverse effects reported under DTT were mild; however, the serious ones that had been observed mandate a profoundly cautious approach when considering it. Triple immunosuppressive therapy and combinations of biologics with emergent therapies such as selective Janus kinase inhibitors, sphingosine-1-phosphate receptor modulators, and anti-interleukin-23 agents, are potential future regimens for children with IBD who are refractory to current therapeutic options. This review provides an update of publications on these issues.

Adipose-Derived Mesenchymal Stem Cells Attenuate Immune Reactions Against Pig Decellularized Bronchi Engrafted into Rat Tracheal Defects

ABSTRACT Decellularized scaffolds are promising biomaterials for tissue and organ reconstruction; however, strategies to effectively suppress the host immune responses toward these implants, particularly those without chemical crosslinking, remain warranted. Administration of mesenchymal stem cells is effective against immune-mediated inflammatory disorders. Herein, we investigated the effect of isogeneic abdominal adipose-derived mesenchymal stem/stromal cells (ADMSCs) on xenogeneic biomaterial-induced immunoreactions. Peripheral bronchi from pigs, decellularized using a detergent enzymatic method, were engrafted onto tracheal defects of Brown Norway (BN) rats. BN rats were implanted with native pig bronchi (Xenograft group), decellularized pig bronchi (Decellularized Xenograft), or Decellularized Xenograft and ADMSCs (Decellularized Xenograft+ADMSC group). In the latter group, ADMSCs were injected intravenously immediately post implantation. Harvested graft implants were assessed histologically and immunohistochemically. We found that acute rejections were milder in the Decellularized Xenograft and Decellularized Xenograft+ADMSC groups than in the Xenograft group. Mild inflammatory cell infiltration and reduced collagen deposition were observed in the Decellularized Xenograft+ADMSC group. Additionally, ADMSC administration decreased CD8+ lymphocyte counts but increased CD163+ cell counts. In the Decellularized Xenograft+ADMSC group, serum levels of vascular endothelial growth factor and IL-10 were elevated and tissue deposition of IgM and IgG was low. The significant immunosuppressive effects of ADMSCs illustrate their potential use as immunosuppressive agents for xenogeneic biomaterial-based implants.

Disposition and Mass Balance of Etrasimod in Healthy Subjects and In Vitro Determination of the Enzymes Responsible for Its Oxidative Metabolism.

Etrasimod (APD334) is an investigational, once-daily, oral, selective sphingosine 1-phosphate receptor 1,4,5 modulator (S1P1,4,5 ) in development for treatment of various immune-mediated inflammatory disorders. The disposition and mass balance of a single 2-mg [14 C]etrasimod dose were evaluated in 8 healthy males. An in vitro study was also conducted to identify etrasimod's oxidative metabolizing enzymes. Peak concentrations of etrasimod and total radioactivity in plasma and whole blood were typically reached 4-7hours postdose. Etrasimod constituted 49.3% of total radioactivity plasma exposure, with multiple minor/trace metabolites making up the remainder. Etrasimod was slowly cleared mainly via biotransformation, predominantly by oxidative metabolism, with unchanged etrasimod recovered in feces accounting for only 11.2% of the dose and none in urine. The mean apparent terminal half-lives of etrasimod and total radioactivity in plasma were 37.8 and 89.0hours, respectively. Mean cumulative recovery of radioactivity in excreta over 336hours was 86.9% of the dose, mostly in feces. The prevalent metabolites eliminated in feces were M3 (hydroxy-etrasimod) and M36 (oxy-etrasimod sulfate), accounting for 22.1% and 18.9% of the dose, respectively. From in vitro reaction phenotyping, the predominant enzymes involved in the oxidation of etrasimod were CYP2C8, CYP2C9, and CYP3A4, with minor contributions from CYP2C19 and CYP2J2.

Cellular indexing of transcriptomes and epitopes by sequencing (CITE-Seq) of peripheral blood to dissect the effect of different spondyloarthropathies

Abstract Spondyloarthritis is a family of immune mediated inflammatory disorders with overlapping articular and extraarticular clinical manifestations and a strong association to human leukocyte antigen (HLA)-B27. Despite a strong association of HLA-B27 with prototypic spondyloarthropathies such as axial spondyloarthritis (axSpA) and acute anterior uveitis (AAU), the underlying mechanisms are not known. Here, we aim to determine whether HLA-B27 associated axSpA and AAU are associated with common or divergent immunological markers in the blood. Previously, we did single cell RNA-seq analysis on a small number of patients with AAU and axSpA, which revealed increase in T cell, MAIT cells and NK cell clusters in AAU patients, whereas axSpA patients had increase in MAIT cells, gd-T cells, ILCs and Tregs and decrease in naïve CD8 T cell clusters, suggesting that distinct signatures maybe associated with axSpA and AAU. Changes in ILCs or MAIT cells may suggest involvement of the gut mucosal surface in pathogenesis. This is consistent with our previous studies showing gut microbial perturbation in clinical samples and in rat model of spondyloarthritis. Leveraging on our preliminary data, we are performing CITE-seq to capture paired transcriptome and cell surface epitope expression in individual PBMCs from 5 subjects each with axSpA, AAU and axSpA+AAU in comparison with healthy individuals (5 HLA-B27 negative and 5 HLA-B27 positive). Since, HLA-B27 allele is also present in healthy population, these analyses will allow us to dissect the effect of host genetics from the disease. These studies represent potential advances in the understanding of spondyloarthritis and may reveal genetic and disease biomarkers associated with axSpA and AAU. TG (principal investigator) is a recipient of research awards from the Spondylitis Association of America, SPARTAN (Spondyloarthritis Research and Treatment Network), GRAPPA (Group for Research and Assessment of Psoriasis and Psoriatic Arthritis), The Collins Medical Trust, Medical Research Foundation of Oregon and, Innovation Award from OHSU. This work was funded in part by the Grandmaison Fund for Autoimmunity Research. JTR is a recipient of the Innovative Research Award, Rheumatology Research Foundation.

MicroRNAs in inflammasomopathies

microRNAs (miRNAs) are small non-coding RNA sequences that negatively regulate the expression of protein-encoding genes at the post-transcriptional level. They play a role in the regulation of inflammatory responses by controlling the proliferation and activation of immune cells and their expression is disrupted in several immune-mediated inflammatory disorders. Among these, autoinflammatory diseases (AID) are a group of rare hereditary disorders caused by abnormal activation of the innate immune system and characterized by recurrent fevers. Major groups of AID are inflammasomopathies, which are associated with hereditary defects in the activation of inflammasomes, cytosolic multiprotein signaling complexes regulating IL-1 family cytokine maturation and pyroptosis. The study of the role of miRNAs in AID is only recently emerging and remains scarce in inflammasomopathies. In this review, we describe the AID and inflammasomopathies, and the current knowledge on the role of miRNAs in disease processes.

The features of developing rat autoimmune pathology with mitochondrial dysfunction

The central role of the mitochondria in energy supply and cell death determines highlight these organelles as one of the promising objects for investigating pathogenesis of immune-mediated inflammatory disorders. The aim: to study features of pathogenesis in rat adjuvant-induced autoimmune pathology separately and in combination with mitochondrial disorders. Materials and methods. Wistar rats were divided into groups of negative control (solvent), positive control (single subcutaneous injection of complete Freunds adjuvant (CAF) at dose of 0.1 ml/200 g body weight), experimental (CAF 0.1 ml/200 g body weight and 5 weeks later with cuprizone 0.2% per feed weight). At the end of experiment (7 weeks), animals were tested in the open field model, euthanized, and biomaterial was collected to measure the relative mass coefficients of internal organs, hematological and histological studies. We calculated the mean, standard error of the mean; comparison of hypotheses was carried out by paired Students t-test. Results. In case of impaired immunological tolerance there was detected reduced rat body weight gain during the study period (negative control +74.7 g, positive control +10.3 g) along with modelled mitochondrial dysfunction, a general decrease in weight by 6.7 g was noted. The magnitude of mass coefficients indicate a relative reduction in mass of liver, kidneys, spleen and thymus in experimental animals. The leukocyte counts ( 109/L) are as follows: negative control 8.680.37, positive control 10.981.03 (p 0.05), experimental group 12.280.63 (p 0.001). No significant changes were found in the leukocyte formula and the red cell lineage. During modelled autoimmune pathology, platelet count increased by 22.5% (p 0.05), whereas after cuprizone was administered it decreased by 6.3% (relative to the negative control). Mitochondrial dysfunction caused an abrupt decrease in motor activity in rats: the number of crossed sectors in positive control animals was 55.506.91, experimental group 44.503.60 (inter-group comparison, p 0.001). Positive control: enlarged lymphatic nodules were found in the spleen, germinal center clarification, wall thickening of the pulpal and central arteries; single foci of hemorrhages in the red pulp. Experimental group: atrophy of lymphoid follicles of varying severity (relative to the groups of negative and positive controls), numerous foci of hemorrhages with hemosiderosis in the red pulp. Conclusion. Mitochondrial dysfunction is accompanied by augmented pathogenetic signs of autoimmune pathology, which can serve as one of the keys to understanding the mechanisms of human autoimmunity.

Cannabinoid WIN55,212-2 reprograms monocytes and macrophages to inhibit LPS-induced inflammation.

Chronic or uncontrolled activation of myeloid cells including monocytes, macrophages and dendritic cells (DCs) is a hallmark of immune-mediated inflammatory disorders. There is an urgent need for the development of novel drugs with the capacity to impair innate immune cell overactivation under inflammatory conditions. Compelling evidence pointed out cannabinoids as potential therapeutic tools with anti-inflammatory and immunomodulatory capacity. WIN55,212-2, a non-selective synthetic cannabinoid agonist, displays protective effects in several inflammatory conditions by mechanisms partially depending on the generation of tolerogenic DCs able to induce functional regulatory T cells (Tregs). However, its immunomodulatory capacity on other myeloid cells such as monocytes and macrophages remains incompletely understood. Human monocyte-derived DCs (hmoDCs) were differentiated in the absence (conventional hmoDCs) or presence of WIN55,212-2 (WIN-hmoDCs). Cells were stimulated with LPS, cocultured with naive T lymphocytes and their cytokine production and ability to induce T cell responses were analysed by ELISA or flow cytometry. To evaluate the effect of WIN55,212-2 in macrophage polarization, human and murine macrophages were activated with LPS or LPS/IFNγ, in the presence or absence of the cannabinoid. Cytokine, costimulatory molecules and inflammasome markers were assayed. Metabolic and chromatin immunoprecipitation assays were also performed. Finally, the protective capacity of WIN55,212-2 was studied in vivo in BALB/c mice after intraperitoneal injection with LPS. We show for the first time that the differentiation of hmoDCs in the presence of WIN55,212-2 generates tolerogenic WIN-hmoDCs that are less responsive to LPS stimulation and able to prime Tregs. WIN55,212-2 also impairs the pro-inflammatory polarization of human macrophages by inhibiting cytokine production, inflammasome activation and rescuing macrophages from pyroptotic cell death. Mechanistically, WIN55,212-2 induced a metabolic and epigenetic shift in macrophages by decreasing LPS-induced mTORC1 signaling, commitment to glycolysis and active histone marks in pro-inflammatory cytokine promoters. We confirmed these data in ex vivo LPS-stimulated peritoneal macrophages (PMΦs), which were also supported by the in vivo anti-inflammatory capacity of WIN55,212-2 in a LPS-induced sepsis mouse model. Overall, we shed light into the molecular mechanisms by which cannabinoids exert anti-inflammatory properties in myeloid cells, which might well contribute to the future rational design of novel therapeutic strategies for inflammatory disorders.

Etrasimod for the treatment of ulcerative colitis.

Sphingosine-1-phosphate (S1P) and its receptor (S1PR) are involved in the pathogenesis of multiple immune-mediated inflammatory disorders, including inflammatory bowel disease. The use of S1PR modulators represents a new therapeutic option for ulcerative colitis patients. Etrasimod is an oral selective S1PR1, S1PR4 and S1PR5 modulator that inhibits the trafficking of lymphocytes from the lymph nodes into the blood. Recently, etrasimod has demonstrated efficacy in the phase II OASIS study and its open-label extension for the treatment of ulcerative colitis patients. This article reviews the mechanism of action of etrasimod and summarizes the available clinical efficacy and safety data regarding etrasimod, which is a promising drug in the treatment of patients with moderate to severe ulcerative colitis.

The Impact of Za’atar Antioxidant Compounds on the Gut Microbiota and Gastrointestinal Disorders: Insights for Future Clinical Applications

Since the gut microbiota plays a pivotal role in host homeostasis and energy balance, changes in its composition can be associated with disease states through the promotion of immune-mediated inflammatory disorders and increasing intestinal permeability, ultimately leading to the impairment of intestinal barrier function. Za'atar is one of the most popular plant-based foods in the Eastern Mediterranean region. Za'atar is a mixture of different plant leaves, fruits, and seeds and contains hundreds of antioxidant compounds, especially polyphenols, and fiber, with pre-clinical and clinical evidence suggesting health-promoting effects in cardiovascular and metabolic disease. Za'atar compounds have also been studied from a gastrointestinal perspective, concerning both gut microbiota and gastrointestinal diseases. Antioxidants such as Za'atar polyphenols may provide beneficial effects in the complex interplay between the diet, gut microbiota, and intestinal permeability. To our knowledge, no studies have reported the effects of the whole Za'atar mixture, however, based on the pre-clinical studies published on components and single compounds found in Za'atar, we provide a clinical overview of the possible effects on the gastrointestinal tract, focusing mainly on carvacrol, rosmarinic acid, gallic acid, and other polyphenols. We also cover the potential clinical applications of Za'atar mixture as a possible nutraceutical in disorders involving the gastrointestinal tract.

P086 Sirtuin 7 inhibitor attenuates colonic mucosal immune activation in mice–potential therapeutic target in Inflammatory Bowel Disease

Abstract Background Accumulating evidence has shown that sirtuin 7 (SIRT7), a mediator of various cellular activities, plays an important role in the pathogenesis of various immune-mediated inflammatory disorders. However, information remains limited regarding the role of SIRT7 in intestinal inflammation. We used a murine colitis model to investigate the role of SIRT7 in intestinal immunity and whether SIRT7 inhibitors could attenuate the intestinal inflammatory response. Methods Mice were divided into three groups: control, colitis-induced, and SIRT7 inhibitor-treated. A colitis mouse model was established by intraperitoneal injection and nasal challenge with ovalbumin, as in our previous study. Quantitative analyses of inflammatory cytokines and SIRT7 levels in the colonic mucosa were performed to compare the changes in inflammatory responses between the three groups. Results The colitis group showed increased levels of inflammatory cytokines and SIRT7 in the colonic mucosa. The inflammatory reaction was suppressed in colitis-induced mice administered SIRT7 inhibitor. The qRT-PCR results showed normalization of inflammatory cytokines in the SIRT7 inhibitor-treated group. Histologic study revealed a decrease in the extent of inflammation after SIRT7 treatment. We also observed that the degree of clinical inflammation was improved in SIRT7-treated mice. Conclusion Our study demonstrated that SIRT7 inhibition attenuated the inflammatory response in the colon of mice, suggesting a possible role for SIRT7 in the pathogenesis of immune-mediated intestinal inflammation.