Treatment Of Autoimmune Inflammatory Diseases Research Articles

TEMPORARY REMOVAL: Self-adaptive pyroptosis-responsive nanoliposomes block pyroptosis in autoimmune inflammatory diseases

Nanoliposomes have a broad range of applications in the treatment of autoimmune inflammatory diseases because of their ability to considerably enhance drug transport. For their clinical application, nanoliposomes must be able to realize on-demand release of drugs at disease sites to maximize drug-delivery efficacy and minimize side effects. Therefore, responsive drug-release strategies for inflammation treatment have been explored; however, no specific design has been realized for a responsive drug-delivery system based on pyroptosis-related inflammation. Herein, we report a pioneering strategy for self-adaptive pyroptosis-responsive liposomes (R8-cardiolipin-containing nanoliposomes encapsulating dimethyl fumarate, RC-NL@DMF) that precisely release encapsulated anti-pyroptotic drugs into pyroptotic cells. The activated key pyroptotic protein, the N-terminal domain of gasdermin E, selectively integrates with the cardiolipin of liposomes, thus forming pores for controlled drug release, pyroptosis, and inflammation inhibition. Therefore, RC-NL@DMF exhibited effective therapeutic efficacies to alleviate autoimmune inflammatory damages in zymosan-induced arthritis mice and dextran sulfate sodium-induced inflammatory bowel disease mice. Our novel approach holds great promise for self-adaptive pyroptosis-responsive on-demand drug delivery, suppressing pyroptosis and treating autoimmune inflammatory diseases.

Population Pharmacokinetics of Oral Brepocitinib in Healthy Volunteers and Patients.

Brepocitinib is a tyrosine kinase 2 and Janus kinase 1 inhibitor in development for treatment of inflammatory autoimmune diseases. This analysis aimed to add to the pharmacokinetic knowledge of the medication, through development of a population pharmacokinetic model and identification of factors that affect drug disposition. Plasma samples from 5 clinical trials were collated, composed of healthy volunteers, patients with psoriasis and patients with alopecia areata taking oral brepocitinib. NONMEM was used to develop a population pharmacokinetic model, and patient demographics were tested as covariates. The final model was a 1-compartment model with first-order absorption. The typical values for apparent clearance and apparent volume of distribution were 18.7 L/h (78% coefficient of variation [CV]) and 136 L (60.5% CV), respectively. Absorption was rapid with an absorption constant of 3.46 h, with an absorption lag of 0.24 hours observed with the oral tablet formulation. The proportional residual error was found to be 52.7% CV in healthy volunteers and 87.5% CV in patients. High-fat meals were associated with a reduction in both the rate (69.9% lower) and extent (28.3% lower) of absorption, while Asian populations had reduced clearance (24.3% lower). Nonlinear pharmacokinetics were observed at doses of 175 mg and above, with a 35.1% higher relative bioavailability at these doses. There were insufficient data to describe this nonlinearity as a continuous relationship. This initial description of the population pharmacokinetics will act as a foundation for the model-informed drug development of brepocitinib and will facilitate future modeling of this medicine. ClinicalTrials.gov numbers NCT02310750 NCT03236493 NCT03656952 NCT02969018 NCT02974868.

Effects of Etanercept on TNF-α Inhibition in Rats with Adenine-Induced Chronic Kidney Disease.

Introduction Chronic kidney disease (CKD) constitutes a chronic inflammatory state associated with an increase in inflammatory mediators and profibrotic molecules such as tumor necrosis factor-α (TNF-α). Etanercept (ETA) is a TNF inhibitor widely used in treatment of autoimmune inflammatory diseases. However, the effects of TNF-α inhibition in the establishment of CKD have not been fully elucidated. We evaluate the effects of TNF inhibition by ETA in adenine- (Ad-) induced CKD in rats. Methods Rats were divided into three groups: control, renal injury model, and model plus ETA (2 mg/kg, 3 times per week (w); sc). Renal injury was induced by Ad administration (100 mg/kg, daily for 2 or 4 w; orogastric). Serum TNF-α levels and biochemical parameters for renal function were evaluated. Histopathological changes in the kidney were assessed using H&E and Masson's trichrome staining and also immunostaining for tubular cells. Results Ad administration produced a renal functional decline, tubular atrophy, interstitial inflammation, and fibrosis for 2 w, followed by renal anemia, several renal dysfunctions, tubular atrophy, and fibrosis at 4 w. A significant increase in serum TNF-α levels was observed from 2 w of Ad administration and remained elevated up to 4 w. Treatment with ETA partially reduced kidney damage but was very effective to blocking serum TNF-α. Conclusion Although inhibition of TNF by ETA was very effective in reducing serum TNF-α, this strategy was partially effective in preventing Ad-induced CKD.

Recent advances on drug delivery nanoplatforms for the treatment of autoimmune inflammatory diseases

As one of the current research hotspots, drug release nanoplatforms have great potential in the treatment of autoimmune inflammatory diseases.

Infection, immunosuppression, and treatment of auto-immune inflammatory kidney disease

Immunosuppressive drugs are the cornerstone of treatment of auto-immune inflammatory diseases (AIIDs) with renal involvement. How‑ ever, the most commonly used drugs in this setting can increase the risk of bacterial, fungal, and viral infection, and also impair immune response following vaccination. Recommendations and evidence on strategies for infection prevention in the setting of AIIDs treatment will be reviewed.

Treating Autoimmune Inflammatory Diseases with an siERN1-Nanoprodrug That Mediates Macrophage Polarization and Blocks Toll-like Receptor Signaling.

The clinical application of small interfering RNA (siRNA) drugs provides promising opportunities to develop treatment strategies for autoimmune inflammatory diseases. In this study, siRNAs targeting the endoplasmic reticulum to nucleus signaling 1 (ERN1) gene (siERN1) were screened. Two cationic polymers, polyethylenimine (PEI) and poly(β-amino amine) (PBAA), which can improve the efficiency of the siRNA transfection, were used as siERN1 delivery carriers. They were implemented to construct a nanodrug delivery system with macrophage-targeting ability and dual responsiveness for the treatment of autoimmune inflammatory diseases. In terms of the mechanism, siERN1 can regulate the intracellular calcium ion concentration by interfering with the function of inositol 1,4,5-trisphosphate receptor 1/3 (IP3R1/3) and thus inducing M2 polarization of macrophages. Furthermore, siERN1-nanoprodrug [FA (folic acid)-PEG-R(RKKRRQRRR)-NPs(ss-PBAA-PEI)@siERN1] acts as a conductor of macrophage polarization by controlling the calcium ion concentration and is an inhibitor of MyD88-dependent Toll-like receptor signaling. The results revealed that the FA-PEG-R-NPs@siERN1 has universal biocompatibility, long-term drug release responsiveness, superior targeting properties, and therapeutic effects in mouse collagen-induced arthritis and inflammatory bowel disease models. In conclusion, this study reveals a potential strategy to treat autoimmune inflammatory disorders.

NETosis in Rheumatic Diseases

Neutrophils are the most numerous and the first responder cells of the innate immune system. Evidence suggests that neutrophils may play an essential role in the pathogenesis of multiple systemic diseases. A novel mechanism of neutrophil extracellular traps (NETs) leading to breaking of self-tolerance and generation of autoimmune responses in predisposed individuals has been described in various autoimmune conditions. The purpose of the review is to identify these important mechanisms of NETs leading to autoimmunity in various rheumatic diseases. NETs contain histone and chromatin, which contain important autoantigens. Many autoimmune conditions are associated with increased NET-generating capacity, unique low-density granulocyte population, and impaired NET degradation leading to persistent inflammation and tissue damage. NETs can also activate other immune cells, and their components may amplify the inflammatory response by activation of complement pathways and inflammasomes. NETs can also contribute to autoantibody formation in disorders such as rheumatoid arthritis, ANCA-associated vasculitis, and systemic lupus erythematosus by providing a constant source of autoantigens. NETs can also serve as biomarkers providing insights into disease diagnosis and therapeutics. NETs seem to play a primary role in inflammatory disease pathogenesis. Identification of different NET pathogenic pathways in various rheumatic conditions could provide new insights into disease pathogenesis and therapeutic targets could be developed towards the future treatment of inflammatory autoimmune diseases.

Filgotinib: First Approval

Filgotinib (Jyseleca®) is an oral, ATP-competitive, reversible JAK1 preferential inhibitor that is being developed by Galapagos NV and Gilead Sciences for the treatment of inflammatory autoimmune diseases, including inflammatory arthritis and inflammatory bowel disease. The JAK-STAT signalling pathway has been implicated in the pathogenesis of inflammatory and autoimmune diseases, and filgotinib modulates this pathway by preventing the phosphorylation and activation of STATs. In September 2020, filgotinib received its first approvals in the EU and Japan. In the EU, filgotinib is indicated for the treatment of moderate to severe active rheumatoid arthritis (RA) in adults who have responded inadequately to, or who are intolerant to, one or more disease-modifying anti-rheumatic drugs (DMARDs). In Japan, filgotinib is indicated for the treatment of RA in patients who had an inadequate response to conventional therapies (including prevention of structural damage to joints). Clinical studies of filgotinib for the treatment of inflammatory autoimmune diseases are ongoing worldwide. This article summarizes the milestones in the development of filgotinib leading to this first approval.

Discovery and optimization of a potent and selective indazolamine series of IRAK4 inhibitors

IRAK4 is a key mediator of innate immunity. There is a high interest in identifying novel IRAK4 inhibitors for the treatment of inflammatory autoimmune diseases. We describe here a highly potent and selective IRAK4 inhibitor (HS271) that exhibited superior enzymatic and cellular activities, as well as excellent pharmacokinetic properties. HS271 displayed robust in vivo anti-inflammatory efficacy as evaluated in rat models of LPS induced TNFα production and collagen-induced arthritis.

AB0039 ROLE OF MESENCHYMAL STEM CELLS ISOLATED FROM DENTAL PULP (DPSCS) IN IMMUNOREGULATION PROCESSES MEDIATED BY PROGRAMMED DEATH-LIGAND 1 (PD-L1)

Background:Stem cells isolated from dental pulp (DPSCs) are characterized by a high rate of proliferation, low immunogenicity and a high ability to differentiate in different lineages (i.e. osteogenic, chondrogenic, adipogenic, myogenic and neural commitment). Their multipotency can be attributed to the peculiar embryological origin from the neural crest. DPSCs represent a promising stem cell resource since they hold a low ethical impact and can be easily isolated through routine dental procedures. These cells own immuno-modulatory properties, exerted through the activation of different mechanisms, including the Fas / FasL pathway, as well as through the release of soluble factors. Currently, other molecular mechanisms are under consideration such as PD-1 / PD-L1 (Programmed Death 1 and its Ligand) which are supposed to be involved in the induction and / or maintenance of immune tolerance.Objectives:The aim of this research was to investigate whether the stimulation of PD-L1 in DPSCs can affect the immunomodulatory effects of these stem cells on peripheral blood mononuclear cells (PBMCs). Furthermore, the expression of PD-L1 was also assayed after the induction of osteogenic differentiation of DPSCs in order to evaluate a possible application of DPSCs in autoimmune inflammatory osteo-erosive diseases.Methods:Immuno-selection was performed on DPSCs, isolated from waste material, against the stemness markers c-Kit and STRO-1, to obtain a pure stem cell population. Then, STRO-1+/c-Kit+ DPSCs, were co-cultured either directly and indirectly with peripheral blood mononuclear cells (PBMCs) from healthy adult donors, previously activated by anti-CD3 and anti-CD28 antibodies. Co-cultures of PBMCs with amniotic fluid stem cells (AFSCs) and bone marrow mesenchymal stem cells (BM-MSCs) were also set up. The expression of PD-1 in PBMCs as well as of PD-L1 in DPSCs, AFSCs, BM-MSCs and PBMCs, was evaluated by Western Blot (WB) and immunofluorescence (IF) analyses, before and after osteogenic differentiation. Osteogenic differentiation of DPSCs, after 30 days of induction, was verified by IF and WB, of osteopontin, osteocalcin and RUNX2 markers. Interleukin-2 (IL-2) expression levels in PBMCs were analyzed by Real-Time PCR analysis.Results:Our data highlight that, after direct and indirect co-culture with activated PBMCs, PD-L1 expression was up-regulated not only in DPSCs, but also in BM-MSCs and AFSCs (Figure 1), thus suggesting that 1) this is a common ability of mesenchymal stem cells and 2) this event can be also mediated by soluble factors release. Moreover, when evaluating the effects of DPSCs co-culture on PBMCs an increased expression of cleaved caspase 3 was observed, together with a decreased expression of IL-2 - a growth factor essential for the proliferation and survival of T cells (Figure 2). These findings showed how DPSCs can modulate the immune system by PD-L1 up-regulation. On the other hand, it is noteworthy that, after reaching osteogenic commitment, DPSCs down-regulated the expression of PD-L1, allowing to hypothesize that PD-L1 expression is strictly related to the maintenance of stemness.Figure 1.Figure 2.Conclusion:Taken together, our findings suggest that the expression of PD-L1 in DPSCs is involved in the modulation of immune response and pave the way for further investigations on the role of PD-1/PD-L1 pathway in controlling inflammation and immune response when applied to the treatment of autoimmune inflammatory diseases.

Impact of the Adalimumab Patient Support Program on Clinical Outcomes in Ankylosing Spondylitis: Results from the COMPANION Study

Adalimumab (ADA) is a tumor necrosis factor (TNF)-alpha inhibitor indicated for the treatment of inflammatory autoimmune diseases, including ankylosing spondylitis (AS). Patients receiving ADA in Canada are eligible to enroll in the AbbVie Care™ patient support program (AC-PSP), which provides personalized services, including care coach calls (CCCs). We estimated the likelihood of controlled disease in a cohort of AS patients treated with ADA enrolled in the AC-PSP and who received CCCs versus those who did not. A longitudinal analysis using de-identified aggregate-level data collected through the AC-PSP was performed. A probabilistic matching algorithm was used to link patient-level records from the AC-PSP database to records from the QuintilesIMS longitudinal prescription transactions database. Patients were indexed on the date of their first prescription of ADA between January 2010 and October 2015. The AC-PSP database included patient assessments of the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), a measure of disease activity. Eligible patients had a baseline BASDAI assessment performed between 90days before and 30days after the index date, and a follow-up BASDAI assessment 6-18months later. Poisson regression was used to estimate the adjusted relative risk (RR) of controlled disease (BASDAI < 4) at the time of follow-up, comparing patients who received CCCs with those who did not. In total 249 AS patients met eligibility criteria, and 123 (49%) received CCCs. Of the 249 patients, 184 (74%) had controlled disease (BASDAI < 4) at follow-up assessment, 98 (80%) in the CCC group and 86 (68%) in the no CCC group. Multivariable regression analysis demonstrated a 23% increased likelihood of controlled disease in patients who received CCCs relative to those who did not (RR = 1.23; 95% confidence interval, 1.06-1.42; p = 0.0055). AS patients receiving tailored services through the AC-PSP in the form of CCCs have an increased likelihood of controlled disease within 6-18months. AbbVie.

Upadacitinib tartrate. Tyrosine-protein kinase JAK1 inhibitor, Treatment of autoimmune inflammatory diseases, Treatment of rheumatoid arthritis

Upadacitinib tartrate. Tyrosine-protein kinase JAK1 inhibitor, Treatment of autoimmune inflammatory diseases, Treatment of rheumatoid arthritis

Molecular Basis for the Neutralization of Tumor Necrosis Factor α by Certolizumab Pegol in the Treatment of Inflammatory Autoimmune Diseases.

Monoclonal antibodies against TNFα, including infliximab, adalimumab, golimumab, and certolizumab pegol, are widely used for the treatment of the inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease. Recently, the crystal structures of TNFα, in complex with the Fab fragments of infliximab and adalimumab, have revealed the molecular mechanisms of these antibody drugs. Here, we report the crystal structure of TNFα in complex with the Fab fragment of certolizumab pegol to clarify the precise antigen-antibody interactions and the structural basis for the neutralization of TNFα by this therapeutic antibody. The structural analysis and the mutagenesis study revealed that the epitope is limited to a single protomer of the TNFα trimer. Additionally, the DE loop and the GH loop of TNFα play critical roles in the interaction with certolizumab, suggesting that this drug exerts its effects by partially occupying the receptor binding site of TNFα. In addition, a conformational change of the DE loop was induced by certolizumab binding, thereby interrupting the TNFα-receptor interaction. A comprehensive comparison of the interactions of TNFα blockers with TNFα revealed the epitope diversity on the surface of TNFα, providing a better understanding of the molecular mechanism of TNFα blockers. The accumulation of these structural studies can provide a basis for the improvement of therapeutic antibodies against TNFα.

IL-33 circulating serum levels are increased in patients with non-segmental generalized vitiligo.

IL-33 is a recently identified cytokine, encoded by the IL-33 gene, which is a member of the IL-1 family that drives the production of T-helper-2 (Th-2)-associated cytokines. Serum levels of IL-33 have been reported to be up-regulated in various T-helper (Th)-1/Th-17-mediated diseases, such as psoriasis, rheumatoid arthritis, and inflammatory bowel. To investigate whether cytokine imbalance plays a role in the pathogenesis of vitiligo, we performed a case-control association study by enzyme-linked immunosorbent assay of IL-33 in our patients. IL-33 serum levels were measured by a quantitative enzyme immunoassay technique in patients with non-segmental generalized vitiligo and compared with those of healthy controls. IL-33 serum levels in patients with vitiligo were significantly increased than those in healthy controls. There was a positive correlation of IL-33 serum levels with extension of vitiligo and disease activity. This study suggests a possible systemic role of IL-33 in the pathogenesis of vitiligo. Inhibiting IL-33 activity might be a novel therapeutic strategy in the treatment of autoimmune inflammatory disease, like vitiligo.

Targeting Th17 Effector Cytokines for the Treatment of Autoimmune Diseases.

Interleukin (IL)-17-producing T cells, especially T helper (Th)17 cells, play a critical role in the pathogenesis of a variety of autoimmune inflammatory diseases. The pathogenic function of Th17 cells results from their production of Th17 effector cytokines, namely IL-17 (or IL-17A), IL-17F, IL-22 and IL-26. The importance of IL-17 has been demonstrated by antibody neutralization studies in both animal models of autoimmune diseases as well as in human clinical trials. This review highlights the current knowledge of the clinical aspects of the Th17 cytokines as well as therapeutic antibodies against IL-17, IL-17F, IL-17 receptor, IL-22, IL-26 and granulocyte macrophage colony-stimulating factor for the future treatment of autoimmune inflammatory diseases.

Designing dapsone polymer conjugates for controlled drug delivery

Polymer–drug conjugates have significantly influenced polymer therapeutics over the last decade via controlled pharmacokinetics. Dapsone (4,4′-diamino diphenylsulphone) is not only widely used in the treatment of leprosy but forms an essential component in the treatment of autoimmune inflammatory diseases and malaria. However, its low bioavailability and non-specific distribution in the body leads to absorption throughout organs including skin, liver, and kidneys that can cause serious side effects. Thus, in this study we report the synthesis of polymer–drug conjugates of dapsone covalently bonded to macromolecular chains towards the development of new bioactive polymeric formulations with anti-inflammatory properties. Dapsone was functionalised with an acrylic moiety in which the acrylamide residue was directly bonded to one of the aromatic rings of dapsone. This functionalisation yielded an unsymmetrical dapsone methacrylamide (DapMA) structure, which on free radical polymerisation and co-polymerisation with HEMA yielded polymers of hydrocarbon macromolecules with pendant dapsone units. Thermal and size-exclusion chromatographic analysis revealed an increase in thermal stabilisation of the homopolymer (p(DapMA)) in comparison to the copolymer (p(Dap-co-HEMA)) with relatively high average molecular weight. The polymer conjugates exhibited high stability with low dapsone release from the polymeric backbone due to hydrolysis. However, a significant anti-inflammatory activity in a nitric oxide inhibition assay confirmed that this property was the consequence of only the macromolecular composition and not related to the release of low molecular weight compounds. Thus, the conjugation of dapsone to macromolecular systems provides a synthetic route to incorporate this drug into polymeric systems, facilitating their development into new anti-inflammatory therapies. Statement of SignificanceThe dapsone-conjugated methacrylic monomer and polymer derivatives with anti-inflammatory properties described are previously unreported. The scientific impact of this work lies in its potential to expand the clinical applications of dapsone toward the development of advanced anti-inflammatory therapies based on polymer-therapeutic approaches. These approaches facilitate the treatment of existing rare auto-immune and other inflammatory related diseases.

Treatment patterns and annual drug costs of biologic therapies across indications from the Humana commercial database.

A variety of biologic therapies are currently used for the treatment of inflammatory autoimmune diseases, including rheumatoid arthritis (RA), psoriasis (PsO), psoriatic arthritis (PsA), and ankylosing spondylitis (AS). These diseases require long-term treatment, and information regarding the use and costs of biologic therapies can be valuable in making treatment and formulary decisions for clinicians and payers. To evaluate current utilization and annual costs of biologic therapies for treatment of RA, PsO, PsA, and AS in a real-world setting. This retrospective observational cohort analysis utilized data from the Humana commercial claims database. Eligible patients had an index (first) claim between February 1, 2008, and September 30, 2011, for abatacept, adalimumab, certolizumab pegol, etanercept, golimumab, infliximab, rituximab, or ustekinumab and a diagnosis of RA, PsO, PsA, AS, or combination of these diseases. Patients with and without a claim for their index therapy within 180 days prior to their index dates were defined as continuing and new patients, respectively. Outcomes included 1-year rates of persistence; rates of restarting, discontinuing, or switching for patients who were not persistent; and annual costs. Costs were based on dose and the October 2013 wholesale acquisition cost (WAC). Total expenditure was calculated as the (total index biologic drug utilization × WAC) + (number of administrations × Medicare fee schedule) + Σ(biologic dose after discontinuation × associated WAC price). Of 2,721 patients analyzed, 1,308 (48%) were new patients, and 1,413 (52%) were continuing patients. Across approved indications, the most commonly used biologics were adalimumab, etanercept, and infliximab. Continuing patients had higher rates of persistence on index therapy than new patients. The mean annual cost [SD] per treated patient for new patients across all indications was numerically lowest for adalimumab ($20,916 [$7,572]), followed by infliximab ($22,516 [$8,460]) and etanercept ($23,567 [$8,314]). The mean annual cost [SD] per treated patient for continuing patients across all indications was numerically lowest for etanercept ($21,508 [$6,769]), followed by infliximab ($22,852 [$11,674]) and adalimumab ($24,341 [$8,906]). The tumor necrosis factor blockers adalimumab, etanercept, and infliximab were the most commonly used biologics across indications. New patients were less persistent than those continuing on therapy. Among new patients, adalimumab had the lowest mean annual cost per treated patient, and etanercept had the lowest mean annual cost per treated patient among those continuing on therapy.

TNFα and IL-1β influence the differentiation and migration of murine MSCs independently of the NF-κB pathway

IntroductionMesenchymal stem cells (MSCs) have the ability to repair and regenerate tissue, home to sites of inflammation, and evade the host immune system. As such, they represent an attractive therapy for the treatment of autoimmune inflammatory diseases. However, results from in vivo murine studies in inflammatory arthritis have been conflicting, and this may be due to the genetic background of the MSCs used. It is known that the inflammatory milieu may influence properties of MSCs and that, in the case of human bone marrow-derived MSCs, this may be mediated by the nuclear factor-kappa-B (NF-κB) pathway. We sought to determine whether pro-inflammatory cytokines altered the differentiation and migration capacity of murine MSCs from different mouse strains and whether this was mediated by NF-κB.MethodsThe differentiation and migration of FVB and BALB/c MSCs were carried out in the presence of varying concentrations of tumor necrosis factor-alpha (TNFα) and interleukin (IL)-1β, and the NF-κB pathway was inhibited in one of two ways: either by transduction of MSCs with an adenoviral vector expressing a super-repressor of NF-κB or by the addition of curcumin to culture media.ResultsBoth BALB/c and FVB MSCs were sensitive to the effect of pro-inflammatory cytokines in vitro. TNFα and IL-1β suppressed BALB/c osteogenesis and adipogenesis and FVB osteogenesis. The migration of both cell types toward media containing fetal bovine serum was augmented by pre-stimulation with either cytokine. In neither cell type were the cytokine effects reversed by abrogation of the NF-κB pathway.ConclusionsThese data show that murine MSCs from different genetic backgrounds may be influenced by an inflammatory milieu in a manner that is not mediated by NF-κB, as is the case for human MSCs. This is not mediated by NF-κB. These findings are important and should influence how in vivo trials of murine MSCs are interpreted and the future development of pre-clinical studies in inflammatory diseases.Electronic supplementary materialThe online version of this article (doi:10.1186/scrt492) contains supplementary material, which is available to authorized users.

Prostaglandin E2 inhibits IL-27 production by bone marrow-derived dendritic cells (CCR6P.281)

Abstract Interleukin-27 (p28/EBI3) is expressed by activated antigen presenting cells and has been shown to have immunosuppressive functions including the inhibition of Th17 cell development and the induction of type 1 regulatory T cells (Tr1). In vivo studies demonstrated the anti-inflammatory effects of IL-27 in murine models of collagen-induced arthritis (CIA), inflammatory bowel disease (IBD), and experimental autoimmune encephalomyelitis. We showed previously that PGE2 has proinflammatory effects in models of CIA and IBD through the stimulation of IL-23 production and subsequent development of Th17 cells. Here we report on a novel proinflammatory function through the inhibition of IL-27 production by LPS-stimulated murine BMDC. A similar effect was observed in the dendritic, macrophage and microglia cell lines DC2.4, RAW264.7 and BV2. We determined that the effect of PGE2 was mediated through EP2/EP4 receptors and induction of cAMP. Studies targeting various downstream signaling pathways are in progress. These studies further elucidate the mechanisms involved in the inflammatory role of PGE2, and might identify additional therapeutic targets for the treatment of inflammatory autoimmune diseases.

Pharmacological Potential of NOX2 Agonists in Inflammatory Conditions

New insights into the role of reactive oxygen species (ROS) show that activators of the phagocyte NADPH oxidase 2 (NOX2) complex have the potential to be therapeutic in autoimmune and inflammatory conditions. It is, however, essential to elucidate the consequence of targeting the NOX2 complex, as it might lead to different outcomes depending on disease context and specificity, dose, and timing of ROS production. Increasing evidence is suggesting that the role of the NOX2 complex is far more complex than previously anticipated. In addition to the well-described antimicrobial response, ROS also have immune and inflammatory regulatory effects. Compounds increasing NOX2-dependent ROS production have been shown to be effective both in preventing and in treating inflammatory manifestations in animal models of autoimmune diseases. Altogether, these results suggest the possibility of activating the NOX2 complex for the treatment of autoimmune inflammatory diseases while restoring and maintaining a balanced ROS regulation. The complexity of the NOX system and the derived ROS is important and must be considered when designing the programs for the development of NOX2-activating drugs, as well as for validation of selected hits, to successfully identify substances effective in treating inflammatory and autoimmune conditions. In addition, it is important to consider the complex downstream immunological effects and safety for drugs that increase the production of ROS. There is a strong potential for the development of ROS-inducing drugs, targeting the NOX2 complex, which are effective and safe, for the treatment of inflammatory autoimmune disorders. In such drug development, one must carefully investigate the pharmaceutical properties, including both efficacy and safety of the drugs. In addition, the immunological pathways of this new treatment strategy need careful examination.