Free IL-18 Research Articles

Interleukin-1 family cytokines and soluble receptors in hidradenitis suppurativa.

Hidradenitis suppurativa (HS) is a chronic skin disease, characterized by clinical inflammation of the hair follicle with the recurrence of abscesses, nodules, and tunnels. Recently, several studies suggested a role of IL-1 family (IL-1F) cytokines in eliciting and sustaining the disease. The aim of this work is to perform a comprehensive analysis of IL-1F cytokines, soluble inhibitors and receptors in a cohort of HS patients not treated with biological agents. Sixteen patients affected by HS and 16 healthy controls were recruited; clinical data were collected and disease severity evaluated by means of the International HS Severity Score System (IHS4). Serum levels of IL-1F cytokines, inhibitors and receptors were measured using a Multiplex Assays. IL-18 and free IL-18 levels were significantly higher in patients vs controls. Among soluble inhibitors, IL-1Ra, IL-1R2 and ST2/IL-1R4 were significantly increased. IL-18, free IL-18 and IL-33 levels are strongly correlated with IHS4. Also the inhibitors IL-1Ra and IL-18BP show a correlation with IHS4. The data obtained in this study confirm the involvement of IL-1F cytokines in mediating the disease and determining its severity and suggest a possible role for IL-18 as novel serum biomarker of active disease.

Plasmatic Inactive IL-18 Predicts a Worse Overall Survival for Advanced Non-Small-Cell Lung Cancer with Early Metabolic Progression after Immunotherapy Initiation.

This ancillary study includes 195 patients with metastatic non-small-cell lung cancer (NSCLC) treated with ICI in monotherapy, either pembrolizumab or nivolumab. Plasmatic levels of IL-18-related compounds, comprising the inhibitor IL-18 binding protein (IL-18BP), the inactive IL-18 (corresponding to IL-18/IL-18BP complex), and the active free IL-18, were assayed by ELISA. Objective tumoral response was analyzed by 18FDG PET-CT at baseline, 7 weeks, and 3 months post treatment induction, using PERCIST criteria. Plasmatic IL-18BP and total IL-18 levels are increased at baseline in NSCLC patients compared with healthy controls, whereas IL-18/IL-18BP complexes are decreased, and free IL-18 levels remain unchanged. Neither of the IL-18-related compounds allowed to discriminate ICI responding to nonresponding patients. However, inactive IL-18 levels allowed to discriminate patients with a first tumor progression, assessed after 7 weeks of treatment, with worse overall survival. In addition, we showed that neutrophil concentration is also a predictive indicator of patients' outcomes with OS (HR = 2.6, p = 0.0001) and PFS (HR = 2.2, p = 0.001). Plasmatic levels of inactive IL-18, combined with circulating neutrophil concentrations, can effectively distinguish ICI nonresponding patients with better overall survival (OS), potentially guiding rapid decisions for therapeutic intensification.

Insights into IL-1 family cytokines in kidney allograft transplantation: IL-18BP and free IL-18 as emerging biomarkers

Proinflammatory cytokines and their inhibitors are involved in the regulation of multiple immune reactions including response to transplanted organs. In this prospective study, we evaluated changes in serum concentrations of six IL-1 family cytokines (IL-1 alpha, IL-1 beta, IL-1RA, IL-18, IL-18BP, and IL-36 beta) in 138 kidney allograft recipients and 48 healthy donors. Samples were collected before transplantation and then after one week, three months and one year, additional sera were obtained at the day of biopsy positive for acute rejection. We have shown, that concentrations of proinflammatory members of the IL-1 family (IL-1β, IL-18, IL-36 β) and anti-inflammatory IL-18BP decreased immediately after the transplantation. The decline of serum IL-1RA and IL-1α was not observed in subjects with acute rejection. IL-18, including specifically its free form, is the only cytokine which increase serum concentrations in the period between one week and three months in both groups of patients without upregulation of its inhibitor, IL-18BP. Serum concentrations of calculated free IL-18 were upregulated in the acute rejection group at the time of acute rejection. We conclude that IL-1 family cytokines are involved mainly in early phases of the response to kidney allograft. Serum concentrations of free IL-18 and IL-18BP represent possible biomarkers of acute rejection, and targeting IL-18 might be of therapeutic value.

Clinical significance of IL-18 and IL-18-binding protein in bone marrow of patients with myelodysplastic syndrome

Objective: To analyze the level and clinical significance of IL-18 and IL-18-binding protein (BP) in the bone marrow of patients with myelodysplastic syndrome (MDS) . Methods: A total of 43 newly diagnosed patients with MDS who were admitted to the Department of Hematology, Tianjin Medical University General Hospital, from July 2020 to February 2021 were randomly selected. The control group consisted of 14 patients with acute myeloid leukemia (AML) and 25 patients with iron-deficiency anemia (IDA). The levels of IL-18 and IL-18 BP in the bone marrow supernatant were measured, and their correlations with MDS severity, as well as the functionality of CD8(+) T cells and natural killer cells, was analyzed. Results: The levels of IL-18, IL-18 BP, and free IL-18 (fIL-18) in the bone marrow supernatant of patients with MDS were higher than in the IDA group. The level of fIL-18 was linearly and negatively correlated with the MDS-International Prognostic Scoring System (IPSS) score. IL-18 receptor (IL-18Rα) expression on CD8(+) T cells in the MDS group was lower than in the IDA group, and the levels of fIL-18 and IL-18Rα were positively correlated with CD8(+) T-cell function in the MDS group. Conclusion: IL-18 BP antagonizes IL-18, leading to a decrease in fIL-18 in the bone marrow microenvironment of patients with MDS, affecting CD8(+) T-cell function, which is closely related to MDS severity; therefore, it may become a new target for MDS treatment.

Ratios between the Levels of IL-18, Free IL-18, and IL-1β-Binding Protein Depending on the Severity and Outcome of COVID-19.

In 89 patients with COVID-19, the ratios between IL-18, free IL-18, and IL-18-binding protein (IL-18BP) were analyzed depending on severity and outcome of the disease. At admission to the hospital, the levels of IL-18 and free IL-18 were significantly higher than 3 months after discharge from the hospital, the levels IL-18BP of being almost the same. In patients with more severe lung injury (computed tomography data), the levels of IL-18 and free IL-18 were higher and IL-18BP levels were lower than in patients with mild and moderate COVID-19. Three months after discharge from the hospital, no differences between these parameters were found. In 9 patients who died in the hospital, free IL-18 levels were significantly higher and IL-18BP levels were lower than in survivors. Thus, high levels of bioactive free IL-18 in combination with low levels of IL-18BP can be indicative of severe inflammatory phase of COVID-19 and the risk of worse clinical outcomes.

Biological and clinical roles of IL-18 in inflammatory diseases.

Several new discoveries have revived interest in the pathogenic potential and possible clinical roles of IL-18. IL-18 is an IL-1 family cytokine with potent ability to induce IFNγ production. However, basic investigations and now clinical observations suggest a more complex picture. Unique aspects of IL-18 biology at the levels of transcription, activation, secretion, neutralization, receptor distribution and signalling help to explain its pleiotropic roles in mucosal and systemic inflammation. Blood biomarker studies reveal a cytokine for which profound elevation, associated with detectable 'free IL-18', defines a group of autoinflammatory diseases in which IL-18 dysregulation can be a primary driving feature, the so-called 'IL-18opathies'. This impressive specificity might accelerate diagnoses and identify patients amenable to therapeutic IL-18 blockade. Pathogenically, human and animal studies identify a preferential activation of CD8+ T cells over other IL-18-responsive lymphocytes. IL-18 agonist treatments that leverage the site of production or subversion of endogenous IL-18 inhibition show promise in augmenting immune responses to cancer. Thus, the unique aspects of IL-18 biology are finally beginning to have clinical impact in precision diagnostics, disease monitoring and targeted treatment of inflammatory and malignant diseases.

Disruption of IL-18 signaling via engineered IL-18BP biologics alleviates experimental cholestatic liver disease

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by progressive inflammation and fibrosis around intrahepatic and extrahepatic bile ducts leading to severe hepatic cirrhosis and high mortality. Although there is an urgent clinical unmet need for PSC, no effective medical therapy has been developed to delay the disease progression until today. IL-18 binding protein (IL-18BP) is well-known to be a natural negative feedback regulator for IL-18, and we have developed a recombinant long-acting IL-18BP referred to as APB-R3 as a therapeutic agent to treat IL-18-related inflammatory diseases. Here, we aimed to study whether disrupted IL-18 signaling by APB-R3 treatment can inhibit PSC injuries in the experimental DDC diet-induced PSC rodent model. First, we found that the amounts of free IL-18 are augmented under PSC condition with increased expression of biliary IL-18 receptors. Administration of APB-R3 effectively attenuated key diagnostic parameters of PSC such as plasma ALP and GGT levels as well as bile acids levels. We also observed that blockade of IL-18 suppressed ductular reactive and proliferative phenotypes of cholangiocytes. Additionally, APB-R3 significantly ameliorated DDC diet-induced periductal fibrosis and transcriptional expressions of pro-fibrotic marker genes. Enhanced senescence associated secretory phenotype (SASP) markers in cholestatic liver disease were diminished by APB-R3 treatment. Our findings clearly demonstrate that the administration of IL-18BP biologics, APB-R3, effectively alleviates DDC diet-induced biliary injuries in rodent PSC model, implying APB-R3 can be a promising therapeutic reagent which warrants clinical human trials as new therapeutic options.

IL-18 Binding Protein-Producing Cells Attenuate Anemia in Murine Macrophage Activation Syndrome.

IL-18 is a pleiotropic immunoregulatory cytokine of the IL-1 family. IL-18 has been identified as a potent IFN-γ inducer in synergy with IL-12 and IL-15 and thus as a powerful Th1 cell-polarizing cytokine. IL-18 activity is regulated by its naturally occurring soluble inhibitor IL-18 binding protein (IL-18BP), the production of which is stimulated by IFN-γ in a negative feedback loop. Circulating levels of IL-18BP are elevated, and unbound bioactive free IL-18 is thus not detectable in the circulation in physiologic conditions. However, emerging evidence indicates that the IL-18/IL-18BP balance could be dysregulated in macrophage activation syndrome (MAS), as mirrored by the presence of free IL-18 in the circulation of patients with MAS. Herein, we sought to identify IL-18BP-producing cells in a murine CpG-induced MAS model using IL-18BP knock-in tdTomato reporter mice. Endothelial cells, tissue-resident macrophages, and neutrophils appeared as major cellular sources of IL-18BP. We also identified extramedullary and medullary early erythroid progenitors as IL-18BP-producing cells in an IFN-γ-dependent manner. This finding suggests a novel regulation of IL-18 activity by erythroid precursors, which are likely involved in the prevention of the negative effects of IL-18 on erythropoiesis. Indeed, coherent invivo and invitro results indicate that IL-18 indirectly impairs erythropoiesis while favoring myelopoiesis and thus contributes to anemia associated with MAS and potentially with other IL-18-driven inflammatory diseases. In conclusion, IL-18BP production by endothelial cells, neutrophils, macrophages, and erythroid precursors attenuates the anemia associated with murine CpG-induced MAS.

Detection of Free Bioactive IL-18 and IL-18BP in Inflammatory Disorders.

The interleukin (IL)-18 cytokine plays an important driver role in a range of autoimmune and inflammatory diseases, as well as cancer. IL-18 is a potent inducer of interferon gamma (IFN-γ), and the bioactivity of IL-18 is regulated by its natural soluble inhibitor, IL-18-binding protein (IL-18BP), which is present at high concentrations in the circulation. Many cell types have been described to secrete IL-18BP, constitutively or under the influence of IFN-γ, thus generating a negative feedback loop for IL-18. Therefore, solely measuring total IL-18 protein levels does not allow to evaluate its biological activity, especially in the context of systemic inflammatory diseases or other circumstances where IL-18BP is present (e.g., samples containing plasma, cells constitutively expressing IL-18BP). Considering there is a critical need to accurately measure the protein levels of both mature, biologically active IL-18 and IL-18BP as biomarkers of disease activity in patients and also stratification for potential anti-IL-18 therapy, in this chapter we provide the latest techniques to measure mature, free, and bioactive IL-18 and IL-18BP in different samples.

Interleukin 18 and IL-18 BP response to Sars-CoV-2 virus infection.

The immune response to the SARS-CoV-2 infection is crucial to the patient outcome. IL-18 is involved in the lymphocyte response to the disease and it is well established its important role in the complex developing of the host response to viral infection. This study aims at the analysis of the concentrations of IL-18, IL-18BP, INF-γ at the onset of the SARS-CoV-2 infection. The serum levels of measured interleukins were obtained through enzyme-linked immunosorbent assay. Furthermore, the free fraction of IL-18 was numerically evaluated. The enrolled patients were divided in two severity groups according to a threshold value of 300 for the ratio of arterial partial pressure of oxygen and fraction of inspired oxygen fraction and according to the parenchymal involvement as evaluated by computerized tomography at the admittance. In the group of patients with a more severe disease, a significant increase of the IL-18, INF-γ and IL-18BP levels have been observed, whereas the free IL-18 component values were almost constant. The results confirm that, at the onset of the disease, the host response keep the inflammatory cytokines in an equilibrium and support the hypothesis to adopt the IL-18BP modulation as a possible and effective therapeutic approach.

Balance between Interleukin-18 and Interleukin-18 binding protein in auto-inflammatory diseases.

Interleukin (IL)-18 is a member of the IL-1 family of cytokines with pleiotropic and potent pro-inflammatory activities that are tightly controlled at the level of production and in the extracellular space. Indeed, IL-18 is translated as a leaderless biologically inert pro-peptide that is cleaved by caspase-1 in its N-terminus domain to become active. Mature Il-18 is then released out of the cells via a phenomenon of inflammatory cell death termed pyroptosis. The biological activity of IL-18 is also regulated by a naturally-occurring soluble inhibitor, IL-18 binding protein (IL-18BP) that binds IL-18 and forms high affinity complexes, thus preventing IL-18 to signal through its cell surface receptors. IL-18BP is present in high amount in the circulation, thus unbound free Il-18 is virtually absent in normal and most pathological conditions. Recent findings showed that IL-18 is present in remarkably high concentrations in some autoinflammatory diseases, including adult-onset Still's disease, systemic juvenile idiopathic arthritis and in various conditions associated with hemophagocytic lymphohistiocytosis/macrophage activation syndrome. Furthermore, elevated levels of free IL-18 are present in correlation with clinical and biological signs of disease activity. Most importantly, some patients with these diseases responded remarkably well to the administration of recombinant human IL-18BP, further indicating the pathogenic role of Il-18 and providing a strong rational for the use of IL-18 inhibitors in some of these difficult to treat auto-inflammatory diseases.

Elevated serum free IL-18 in neuropsychiatric systemic lupus erythematosus patients with seizure disorders

Since dysregulation of total Interleukin (IL)-18 and IL-18 binding protein (IL-18BP) may participate in systemic lupus erythematosus (SLE) and contribute to the occurrence of non-autoimmune epilepsy, the aim of the current work is to investigate whether the interaction between IL-18 and IL-18BP plays any role in neuropsychiatric systemic lupus erythematosus related seizures. Data from 137 SLE patients and 30 healthy controls (HC) were consecutively collected from 2020 to 2021. Serum levels of total IL-18 and IL-18BP for all patients and HC were measured by ELISA test. Free IL-18 was calculated based on the law of mass action. Among the 137 SLE patients, 103 had active disease and were classified into NPSLE (n = 50) and Non-NPSLE (n = 53) groups. Among the NPSLE patients, 16 had seizure disorders. Serum free IL-18 levels were increased in NPSLE (277.6 [150.9-428.8]pg/mL) and were correlated with disease activity (r = 0.268, p = 0.002). Moreover, serum free IL-18 levels in NPSLE patients with seizure disorders (350.9 [237.9-455.9]pg/mL) were significantly higher than the levels in those with other neuropsychiatric symptoms (237.7 [124.6-428.8] pg/mL). The expression of free IL-18 was increased in neuropsychiatric systemic lupus erythematosus(NPSLE), especially in NPSLE related seizures. Also, serum levels of free IL-18 were significantly increased in active SLE patients. In this regard, free IL-18 may be involved in the pathogenesis of NPSLE related seizures and associated with disease activity.

IL-18 binding protein (IL-18BP) as a novel radiation countermeasure after radiation exposure in mice

Recent studies suggested that radiation exposure causes local and systemic inflammatory responses and induces cell and tissue damage. We have reported that IL-18 plays an important role in radiation-induced injury. Here, we demonstrate that IL-18 binding protein (IL-18BP), a natural antagonist of IL-18, was significantly increased (1.7–63 fold) in mouse serum on day 1 after 0.5–10 Gy TBI. However, this high level of IL-18BP was not sufficient to neutralize the active IL-18 in irradiated mice, resulting in a radiation dose-dependent free IL-18 increase in these mice’s serum which led to pathological alterations to the irradiated cells and tissues and finally caused animal death. Administration of recombinant human (rh) IL-18BP (1.5 mg/kg) with single (24, 48 or 72 h post-TBI) or double doses (48 h and 5 days post-TBI) subcutaneous (SC) injection increased 30-day survival of CD2F1 mice after 9 Gy TBI 12.5–25% compared with the vehicle control treated group, respectively. Furthermore, the mitigative effects of rhIL-18BP included balancing the ratio of IL-18/IL-18BP and decreasing the free IL-18 levels in irradiated mouse serum and significantly increasing blood cell counts, BM hematopoietic cellularity and stem and progenitor cell clonogenicity in mouse BM. Furthermore, IL-18BP treatment inhibited the IL-18 downstream target interferon (IFN)-γ expression in mouse BM, decreased reactive oxygen species (ROS) level in the irradiated mouse heart tissues, attenuated the stress responsive factor GDF-15 (growth differentiation factor-15) and increased the intestine protector citrulline level in total body irradiated mouse serum, implicating that IL-18BP may protect multiple organs from radiation-induced inflammation and oxidative stress. Our data suggest that IL-18 plays a key role in radiation-induced cell and tissue damage and dysfunction; and for the first time demonstrated that IL-18BP counters IL-18 activation and therefore may mitigate/treat radiation-induced multiple organ injuries and increase animal survival with a wider therapeutic window from 24 h and beyond after lethal doses of radiation exposure.

Production of IL-18 Binding Protein by Radiosensitive and Radioresistant Cells in CpG-Induced Macrophage Activation Syndrome

IL-18 binding protein (IL-18BP) acts as a naturally occurring IL-18 decoy receptor. If the balance between IL-18 and IL-18BP is dysregulated, abnormal levels of free bioactive IL-18 are detected, such as in the sera of Il-18bp knockout (KO) mice with CpG-induced macrophage activation syndrome. To determine the cellular sources of Il-18bp in vivo, we selectively depleted Il-18bp expression in either radiosensitive or radioresistant cells using bone marrow transfer between wild-type (WT) and Il-18bp KO mice. Following repeated CpG injections, Il-18bp KO (donor)→ Il-18bp KO (recipient) chimeric mice exhibited more severe disease, with an enhanced Ifn-γ signature and circulating free Il-18 levels, in comparison with WT→WT chimeras. Interestingly, the phenotype of KO→WT and WT→KO mice did not differ from that of WT→WT mice. Consistent with this finding, serum Il-18bp levels were similar in these three groups of mice. The contribution of radioresistant and radiosensitive cells to Il-18bp production varied markedly according to the organ examined, with a major contribution of radiosensitive cells in the spleen as opposed to a major contribution of radioresistant cells in the lung. Finally, Ifn-γ blockade abrogated the CpG-induced but not the constitutive Il-18bp production. Our results demonstrate that circulating Il-18bp is induced in response to Ifn-γ during CpG-induced macrophage activation syndrome and is present at high levels in the circulation to prevent the deleterious systemic effects of Il-18.

High serum free IL-18 is associated with decreased omalizumab efficacy: findings from a 2-year omalizumab treatment study

Objective Omalizumab is more effective in severe allergic patients with eosinophilic asthma than those with non-eosinophilic asthma. IL-18, a unique cytokine involved in allergic but non-eosinophilic inflammation, might be associated with the latter condition. We aimed to clarify the roles of IL-18 related pathways in insufficient response to omalizumab treatment. Methods Patients with severe allergic asthma who completed 2-year omalizumab treatments at Kyoto University Hospital were included in this study (UMIN000002389). Associations between pretreatment levels of serum free IL-18 in addition to other mediators and asthma phenotypes including responses to omalizumab treatment were analyzed. Changes in serum free IL-18, periostin and total IgE levels during the treatment were also examined. Results Twenty-seven patients (19 females, average age of 55.7 years) were examined. Fifteen incomplete responders who experienced exacerbations in the second year, were significantly and more frequently obese and showed significantly earlier asthma onset, lower blood eosinophils and more exacerbations before omalizumab treatment than complete responders. Significantly more patients showed high baseline serum free IL-18 levels (≥141 pg/mL, a threshold for the highest tertile) among the incomplete responders than complete responders. Patients with high serum free IL-18 levels shared similar characteristics with incomplete responders, showing significant reductions in serum total IgE levels during omalizumab treatment. Finally, serum free IL-18 levels negatively correlated with serum periostin levels at baseline and in change ratios. Conclusions High baseline serum free IL-18 levels may predict reduced omalizumab efficacy in severe allergic patients with type-2 low asthma, regarding reduction of exacerbations.

IL-18/IL-37/IP-10 signalling complex as a potential biomarker for discriminating active and latent TB.

Currently, there are serious limitations in the direct diagnosis of active tuberculosis (ATB). We evaluated the levels of the IL-18/IL-37/IP-10 signalling complex proteins in Mycobacterium tuberculosis (M.tb)-specific antigen-stimulated QuantiFERON® Gold In-Tube (QFT) cultures and in serum samples from ATB patients, healthy individuals with latent M.tb infection (LTBI) and healthy controls (HC) to examine whether combined analyses of these proteins were useful in the differentiation of M.tb states. The concentrations of IL-18, IL-18BP, IFN-γ, IL-37 and IP-10 in the serum and QFT supernatants were measured using specific enzyme-linked immunosorbent assay (ELISA) kits. Free IL-18 levels were calculated using the law of mass action. Increased concentrations of total and free IL-18, IL-18BP, IFN-γ and IP-10 in the sera of ATB patients were detected. These increases were not counterbalanced by the overproduction of IL-37. Complex co-expression of serum IL-18BP and IL-37, IP-10 and IFN-γ was identified as the highest discriminative biomarker set for the diagnosis of ATB. Our results suggest that the IL-18 signalling complex might be exploited by M. tuberculosis to expand the clinical manifestations of pulmonary TB. Therefore, direct analysis of the serum components of the IL-18/IL-37 signalling complex and IP-10 may be applicable in designing novel diagnostic tests for ATB.

High Pre-Transplant Free Interleukin-18 Is Associated with Poor Hematopoietic Recovery after Allogeneic Stem Cell Transplantation

Background: Interleukin-18 (IL-18) is an immune regulatory cytokine that induces interferon-gamma (IFNg) and IL-17A production. The serum activity of IL18 is controlled by an IFNg-inducible inhibitor (IL-18 binding protein, IL18BPa). IL-18 promotes hematopoietic stem cell (HSC) hibernation and aggravates symptoms of sepsis. Here, we investigated whether free IL-18 serum levels measured before and on day 0 of allogeneic stem cell transplantation (alloSCT) inhibit hematologic recovery. Patients and methods: Serum levels of pre-transplant IL-18 and IL18BPa, together with the IFNg-response marker CXCL9, were analyzed in patients from two independent institutions (cohort I n=617 and cohort II n= 605), and in 43 normal subjects. Further, IL-18 and IL18BPa levels were measured also on day 0-3 of alloSCT in 309 patients. Free IL-18 was calculated according to the law of masses. Routine lab parameters were recorded pre-transplant and on days 0, 28 and 100 after alloSCT. These were compared to cytokine serum levels and outcome. Results: Pre-conditioning serum levels of total IL-18 were significantly (approximately threefold) higher in both patient cohorts (cohort I: 629 pg/ml, cohort II: 693 pg/ml) compared to healthy controls (median: 147 pg/ml). Cytokine serum levels further increased by approx. 25% until day 0-3. Pre-transplant IL-18 and free IL-18, but not IL18BPa or CXCL9 were inversely correlated with platelet counts before and on days 28 and 100 after alloSCT in both independent cohorts. This inhibitory effect on platelet recovery was similar for free IL-18 levels measured at the day of transplantation (Figure 1). High free IL18 on day 0-3 and low platelet counts on days 28 and 100 predicted 1-year non-relapse mortality in separate multivariable Cox regression analyses (confounders: age, disease stage, HLA-mismatch, donor and recipient sex, disease, ATG and conditioning strength). Conclusion: Serum levels of free IL-18 were closely associated with platelet recovery after alloSCT. This effect did not depend on the IFNg response markers IL18BPa and CXCL9, suggesting a direct inhibitory effect of IL18 on thrombopoiesis. Strategies reducing IL18 activity should be explored to potentially improve hematopoietic recovery and outcome after alloSCT. Figure 1: ROC curves showing influence of free IL-18 serum levels measured before alloSCT and on day 0-3 on endpoint platelets<50/nl on day+28 Figure 1 Disclosures Bogdanov: Jazz Pharmaceuticals, MSD.: Other: Travel subsidies. Beelen:Medac GmbH Wedel Germany: Consultancy, Honoraria. Dreger:AbbVie, AstraZeneca, Gilead, Janssen, Novartis, Riemser, Roche: Consultancy; AbbVie, Gilead, Novartis, Riemser, Roche: Speakers Bureau; Neovii, Riemser: Research Funding; MSD: Membership on an entity's Board of Directors or advisory committees, Other: Sponsoring of Symposia. Luft:Neovii: Research Funding; JAZZ: Research Funding.

Interleukin-18 and outcome after allogeneic stem cell transplantation: A retrospective cohort study.

BackgroundInterleukin-18 (IL-18) is involved in endothelial activation and dysfunction, and in the pathogenesis and severity of acute graft-versus-host disease (aGVHD). Its relevance for patient outcome after allogeneic stem cell transplantation (alloSCT) has not yet been comprehensively addressed.MethodsPre-transplant serum levels of free IL-18 were retrospectively assessed in a cohort of 589 patients (training cohort). Results were validated in 688 patients allografted in a different centre. The primary endpoint was overall survival (OS). Secondary endpoints included incidences of non-relapse mortality (NRM), relapse, and aGVHD.FindingsIn the training cohort, higher pre-transplant levels of free IL-18 were significantly associated with worse OS (hazard ratio [HR] per 1-log2 increase, 1.25, P = 0.008) in multivariable models. This was due to a higher hazard of NRM (HR per 1-log2 increase, 1.39, P = 0.001), rather than relapse. The associations of pre-transplant free IL-18 with higher NRM (HR per 1-log2 increase, 1.24, P = 0.02) and shorter OS (HR per 1-log2 increase, 1.22, P = 0.006) were confirmed in the validation cohort. In both cohorts, the correlations of higher pre-transplant free IL-18 serum levels with increased NRM and worse OS were mainly driven by fatal infectious complications. No associations with incidence of aGVHD were observed.InterpretationHigher pre-transplant levels of free IL-18 were associated with non-relapse and overall mortality after alloSCT. Our results may provide a rationale for prospective studies evaluating IL-18 status and inhibition of IL-18 activity in patients undergoing allografting.

Interleukin-18 in pediatric rheumatic diseases.

IL-18 is a pleiotropic cytokine involved in the regulation of innate and adaptive immune responses. IL-18 pro-inflammatory activities are finely regulated in vivo by the inhibitory effects of the soluble IL-18-binding protein (IL-18BP). The elevation of circulating levels of IL-18 has been described in children with systemic juvenile idiopathic arthritis (sJIA). In the recent years, the role of IL-18 in the pathogenesis of secondary haemophagocytic lymphohistiocytosis (sHLH), also referred to as macrophage activation syndrome (MAS), in the context of autoinflammatory diseases, including sJIA, is emerging. A large number of studies in patients and animal models pointed to the imbalance in IL-18/IL-18BP levels, causing increased systemic levels of free bioactive IL-18, as a predisposing factor in the development of MAS. Although the exact mechanisms involved in the development of MAS are not clearly understood, increasing evidence demonstrate the role of IL-18 in upregulating the production of interferon (IFN)-γ. On the basis of the first emerging data on the possibility of blocking IL-18, we here discuss the scientific rationale for neutralizing the IL-18/IFNγ axis in the prevention and treatment of sHLH and MAS.

Recurrent inflammatory disease caused by a heterozygous mutation in CD48

Recurrent inflammatory disease caused by a heterozygous mutation in CD48