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Biomedical subjects

D Novick

Publications and source records attributed to D Novick.

At least 19 recordsLinked to original sources

Analysis of hospitalizations comparing rifaximin versus lactulose in the management of hepatic encephalopathy.

INTRODUCTION: Patients with end-stage liver disease often develop hepatic encephalopathy. The loss in cognitive abilities results in marked economic loss to the patient and health care community. We report hospital admission rates and economic impact of patients with end-stage liver disease suffering from hepatic encephalopathy. METHODS: The medical records were reviewed involving liver transplant patients started on lactulose or rifaximin therapy after presenting with stage 2 hepatic encephalopathy from January 2004 to November 2005. Information collected included demographics, hospitalizations required for hepatic encephalopathy, economic data, and Model for End-stage Liver Disease (MELD) score. RESULTS: Thirty-nine patients met study criteria: 24 patients treated with lactulose (group one) and 15 with rifaximin (group two). Group one included 18 men and six women of mean age 48 (range 39 to 58), average MELD 14 (range 10 to 19). Group two included 10 men and five women of mean age 47 (range 42 to 58), average MELD 15 (range 10 to 19). Group one patients required 19 hospitalizations overall: three patients with three hospitalizations, four patients with two hospitalizations, and two patients required one hospitalization. Total drug cost per month was 50 dollars(group one) and 620 dollars(group two). The average annual cost of hospitalization, emergency room visit, and drug per patient treated was 13,284.96 dollars for a total of 318,839 dollars (range 5005 dollars to 26,255 dollars, including drug cost and hospital care). Group two required three hospitalizations, all three with one visit. The average annual cost of hospitalization, emergency room visit, and drug per patient treated was 7958.13 dollars for a total of 119,372 dollars (range 6005 dollars to 19,255 dollars, including drug cost and hospital care). The total cost of therapy per patient per year was 13,285 dollars (group one) versus 7958 dollars (group two). The average length of stay was shorter in group two [3.5 days (range 3 to 4)] versus group 1 [5.0 days (range 3 to 10); P < .0001]. CONCLUSION: These pilot data demonstrate the marked difference in economic costs for the treatment of hepatic encephalopathy. The results also show that in comparative groups, the economic gains are quickly lost when using lactulose.

Adult↗

The impact of prolonged strenuous endurance exercise on interleukin 18 and interleukin 18 binding protein in recreational cyclists.

Interleukin 18 (IL-18) is an important pro-inflammatory cytokine in the early phase of human immune response to microbial infections. The influence of strenuous exercise on the intrinsic balance of IL-18 and its endogenous antagonist IL-18 binding protein (IL-18 BP) is unknown, but could be of major relevance for the athlete's immune function empirically and epidemiologically proven to be altered after exhaustive exertion. To study the effect of strenuous marathon cycling on the interaction of IL-18 and IL-18 BP we investigated 37 male, healthy, and well-trained amateur cyclists participating in the Otztaler Radmarathon in Tyrol (distance: 230 km; cumulative altitude difference: 5500 m). IL-18 was measured by a commercially available ELISA-Kit and IL-18 BP by a novel IL-18 BP ELISA method. Free, unbound IL-18 was calculated according to a standard equation. The mean plasma level of IL-18 was 142.27 +/- 21.85 pg/ml pre-race, remained nearly unchanged (124.35 +/- 13.16 pg/ml; p = 1.0) immediately after competition (mean race time 9 h 38 min), but declined significantly 24 h afterward (62.92 +/- 6.80 pg/ml; p = 0.002). The plasma levels of IL-18 BP increased considerably immediately after and kept on rising for the following 24 h (pre-race: 1.51 +/- 0.20 ng/ml; immediately post-race: 3.84 +/- 0.26 ng/ml, p < 0.001; 24 h post-race: 4.33 +/- 0.42 ng/ml, p < 0.001). Therefore, the calculated free IL-18 was 122.06 +/- 16.79 pg/ml pre-race, declined to 82.86 +/- 8.59 (p = 0.05) immediately post-race and to 39.17 +/- 3.76 pg/ml 24 h post-race (p < 0.001). The respective percentages of this post-exercise reduction in free IL-18 plasma levels were 32 % and 68 %. The present study reveals an exercise-induced significant decline in free IL-18 accompanied by an immediate up-regulation of IL-18 BP and decreased IL-18 in marathon cyclists. This down-regulation of free IL-18 may (i) limit the magnitude and duration of a too excessive inflammatory response to the exercise-induced tissue damage and (ii) on the other hand contribute to the elevated susceptibility to infection in athletes undergoing exhaustive exercise.

Adult↗

Effectiveness of antipsychotic treatment for schizophrenia: 6-month results of the Pan-European Schizophrenia Outpatient Health Outcomes (SOHO) study.

OBJECTIVE: To present the 6-month outcomes associated with antipsychotic treatment of patients participating in the Schizophrenia Outpatient Health Outcomes (SOHO) study. METHOD: SOHO is a 3-year, prospective, observational study of the health outcomes associated with antipsychotic treatment in 10 European countries. The study included over 10,000 out-patients who were initiating or changing their antipsychotic medication. RESULTS: Clinical Global Impression (CGI)-severity and quality of life (QOL) scores improved in all treatment cohorts. There was a higher response in the CGI-overall symptoms and in the CGI-schizophrenia positive, negative, cognitive and depressive symptom scales in the olanzapine (Olz) and clozapine (Cloz) cohorts compared with other treatment cohorts. Changes were associated with an improvement in QOL. CONCLUSION: Patients starting Olz and Cloz tend to have better outcomes at 6 months than patients who start other antipsychotics in actual out-patient clinical practice. The results should be interpreted conservatively because of the non-randomized study design.

Adult↗

Olanzapine vs. other antipsychotics in actual out-patient settings: six months tolerability results from the European Schizophrenia Out-patient Health Outcomes study.

OBJECTIVE: The European Schizophrenia Out-patient Health Outcomes study is an observational study investigating treatment in schizophrenia. We report treatment-emergent adverse events during the first 6 months of treatment. METHOD: The rate of extrapyramidal symptoms (EPS), anticholinergic use, weight gain and sexual related dysfunctions were assessed in 8,400 out-patients. RESULTS: Patients typical antipsychotics and risperidone experienced significantly more EPS and anticholinergic use than patients in the clozapine, olanzapine, and quetiapine cohorts. Patients treated with amisulpride, typical antipsychotics and risperidone were significantly more likely to have sexual related dysfunctions and/or amenorrhea. Increases in weight and body mass index occurred in all cohorts, but were significantly greater in the olanzapine and clozapine cohorts. CONCLUSION: Patients treated with olanzapine, quetiapine and clozapine had better tolerability outcomes regarding EPS and sexual related dysfunctions compared with patients receiving risperidone, amisulpride and typicals. Patients treated with olanzapine and clozapine had higher weight increases than patients treated with risperidone, quetiapine and typicals.

Adult↗

Personality pathology and outcome in recurrently depressed women over 2 years of maintenance interpersonal psychotherapy.

BACKGROUND: Empirical data on the impact of personality pathology on acute treatment outcome for depression are mixed, in part because of challenges posed by assessing trait-like personality patterns while patients are in an active mood episode. To our knowledge, no previous study has examined the effect of personality pathology on maintenance treatment outcome. By maintenance treatment we refer to long-term treatment provided to prevent depression recurrence among remitted patients. METHOD: Structured Clinical Interviews for the DSM-III-R Personality Disorders (SCID-II) were obtained on a sample of 125 recurrently depressed women following sustained remission of the acute mood episode and prior to entering maintenance treatment. SCID-II interviews were then repeated following 1 and 2 years of maintenance interpersonal psychotherapy. RESULTS: At the pre-maintenance assessment, 21.6% of the sample met SCID-II personality disorder criteria. Co-morbid personality pathology was related to an earlier age of onset, more previous depressive episodes, and a greater need for adjunctive pharmacotherapy to achieve remission of the acute mood episode. Co-morbid personality pathology predicted both higher rates of depression recurrence and a shorter time to recurrence over the 2-year course of maintenance treatment. Notably, among those patients who remained depression-free, continuous levels of personality pathology steadily declined over the 2-year course of maintenance therapy. CONCLUSIONS: Results highlight the need for early and effective intervention of both episodic mood disorder and inter-episode interpersonal dysfunction inherent to the personality disorders. Future maintenance treatment trials are needed to clarify the relationship between episodic mood disorder and personality function over time.

Adult↗

Financing health care in Europe: context for the Schizophrenia Outpatient Health Outcomes Study.

OBJECTIVE: Exploration of the implications for mental health care of the health care funding environment in Europe, as context for the Schizophrenia Outpatient Health Outcomes (SOHO) Study. METHOD: Data on health care financing for individual countries were sourced by review of the literature and personal communication with European country representatives. RESULTS: The main and complementary sources of health care finance are presented for the 10 European countries participating in the SOHO study. CONCLUSION: A mixture of tax and social insurance funding mechanisms dominate general health care funding in Europe. These mechanisms in principle promote equity in access to all health care interventions, including those for mental health. However, current resource allocation to mental health care may not reflect fully the impact of mental health disorders. Further work is now under way to examine the contribution of non-health sectors (such as social welfare) to the funding and provision of services.

Ambulatory Care↗

The Clinical Global Impression-Schizophrenia scale: a simple instrument to measure the diversity of symptoms present in schizophrenia.

OBJECTIVE: To describe the development and validation of the Clinical Global Impression-Schizophrenia (CGI-SCH) scale, designed to assess positive, negative, depressive and cognitive symptoms in schizophrenia. METHOD: The CGI-SCH scale was adapted from the CGI scale. Concurrent validity and sensitivity to change were assessed by comparison with the Positive and Negative Symptom Severity (PANSS) and Global Assessment of Functioning (GAF) scales. To evaluate inter-rater reliability, all patients were assessed by two clinicians. RESULTS: Symptoms were assessed in 114 patients. Correlation coefficients between the CGI-SCH and the GAF and PANSS scores were high (most above 0.75), and were highest for positive and negative symptoms. Reliability was substantial (intraclass correlation coefficient, ICC > 0.70) in all but one dimension (depressive dimension, ICC = 0.64). CONCLUSION: The CGI-SCH scale is a valid, reliable instrument to evaluate severity and treatment response in schizophrenia. Given its simplicity, brevity and clinical face validity, the scale is appropriate for use in observational studies and routine clinical practice.

Adult↗

A Rasch model analysis to test the cross-cultural validity of the EuroQoL-5D in the Schizophrenia Outpatient Health Outcomes Study.

OBJECTIVE: To investigate the pan-European, cross-cultural validity of the EuroQol-5D (EQ-5D) for assessing quality of life in the Schizophrenia Outpatient Health Outcomes (SOHO) Study. METHOD: The EQ-5D items investigated were mobility, self-care, usual activities, pain/discomfort and anxiety/depression. A Rasch rating scale model (a form of differential item functioning) was used to identify invariance of item calibrations for the 10 European countries participating in the SOHO study. RESULTS: There was general congruence in the EQ-5D item calibration pattern. The rank of average EQ-5D item calibrations was similar for all countries except Denmark. Denmark showed slight misfits for mobility and pain/discomfort. CONCLUSION: The EQ-5D is an appropriate measure of health-related quality of life across European countries and translations.

Adult↗

High circulating levels of biologically inactive IL-6/SIL-6 receptor complexes in systemic juvenile idiopathic arthritis: evidence for serum factors interfering with the binding to gp130.

We previously demonstrated that high levels of IL-6/sIL-6R complexes are present in sera of patients with systemic juvenile idiopathic arthritis (s-JIA) and that the amount of IL-6 estimated in the IL-6/sIL-6R complexes is markedly higher than that measured by the B9 assay. Here, we show that two additional bioassays, employing human myeloma XG-1 cells and human hepatoma Hep3B cells, detected serum IL-6 levels similar to those measured by the B9 assay and approximately 10-fold lower than the IL-6 levels estimated to be present in the IL-6/sIL-6R complex. Using an assay for the measurement of the amount of circulating IL-6 complexed with the sIL-6R and available for binding to gp130 (gp130 binding activity), we show that the IL-6/gp130 binding activity is similar to that detected by the bioassays and again significantly lower than that estimated to be present in the IL-6/sIL-6R complex. Addition of recombinant human IL-6 (rhIL-6) to sera of patients or controls results in a markedly lower increase in the gp130 binding activity in patients than in controls. Moreover, sera from s-JIA patients inhibited in a dose dependent manner the gp130 binding activity assay. These results show that sera from patients with s-JIA contain a factor, or factors, that inhibit(s) the binding of the IL-6/sIL-6R complex to gp130. This inhibitory activity does not appear to be due to soluble gp130, C-reactive protein or autoantibodies to IL-6.

Adolescent↗

Interleukin-18, interleukin-18 binding protein and impaired production of interferon-gamma in chronic renal failure.

UNLABELLED: Uremia is associated with suppressed cellular immune responses, manifested, in part, by impaired interferon-gamma (IFNgamma) production. We investigated the influence of kidney function on plasma levels of interleukin-18 binding protein (IL-18BP), the naturally occurring inhibitor of IL-18. METHODS: Plasma levels of IL-18, IL-18BP and IFNgamma were measured by specific immunoassays in patients with normal kidney function (NKF, n = 29), in patients with chronic renal insufficiency (CRI, n = 29), and in patients on hemodialysis (HD, n = 40). In addition, Staphylococcus epidermidis-induced production of IFNgamma and IL-18 in whole blood cultures was determined in 12 patients on HD and compared to production in 9 controls with NKF. RESULTS: Plasma IL-18 (mean +/- SEM) in NKF was 17.9 +/- 3.6 pg/ml, in CR142.6 +/- 7.0 pg/ml (p < 0.01), and in HD 93.5 +/- 13.6 pg/ml (p < 0.001). The level of IL-18BP in NKF was 3.4 +/- 0.4 ng/ml, in CRI 7.5 +/- 0.7 ng/ml (p < 0.001), and in HD 13.1 +/- 0.8 ng/ml (p < 0.001). Plasma IL-18BP was inversely correlated with creatinine clearance (correlation coefficient: -0.7479). The level of free IL-18 was calculated in NKF to be 13.8 +/- 3.3 pg/ml, in CRI 23.6 +/- 3.9 pg/ml (not significant), and in HD 39.6 +/- 5.9 pg/ml (p < 0.001). Stimulated whole blood production of IFNgamma in NKF was 185 +/- 74 pg/10(6) mononuclear cells (PBMC), but suppressed in HD to 27.3 +/- 16 pg/10(6) PBMC (p < 0.05). CONCLUSION: In uremia, retention of IL-18BP does not suffice to neutralize most of the concomitantly raised levels of total IL-18 resulting in elevated levels of free IL-18. Nevertheless, IFNgamma production in whole blood is reduced in patients on HD. Therefore, suppression of IFNgamma production in uremia may be due to inhibitors of IFNgamma production other than IL-18BP.

Adult↗

Interferon-alpha induces interleukin-18 binding protein in chronic hepatitis C patients.

Interleukin-18 (IL-18), derived from macrophages and Kupffer cells, is the central pro-inflammatory cytokine leading to experimental liver failure. IL-18 binding protein (IL-18BP) is a circulating protein that binds IL-18 and neutralizes its activity. Since IL-18 production is increased in chronic HCV infection, we asked whether IFN-alpha might act on the IL-18/IL-18BP system in HCV patients. IL-18BP, total and free IL-18 plasma levels were determined in 13 HCV patients receiving 1 x 107 IU IFN-alpha subcutaneously daily for 28 days. The in vitro effects of IFN-alpha on macrophage IL-18BP and IL-18 were studied by enzyme-linked immunosorbent assays and Northern analysis. IFN-alpha administration increased IL-18BP plasma levels 3.24 fold 24 h after institution of therapy, resulting in a 67.4% reduction of free IL-18. Total IL-18 levels decreased from day +24 on. In vitro, IFN-alpha diminished IL-18 release from macrophages of healthy volunteers and chronic HCV patients. On top of its inhibitory effects on IL-1 and TNF-alpha release, IFN-alpha also exerts its anti-inflammatory action in vivo by induction of IL-18BP. These anti-inflammatory properties might account - together with its antiviral action - for its clinical efficacy in chronic hepatitis C.

Down-Regulation↗

A novel IL-18BP ELISA shows elevated serum IL-18BP in sepsis and extensive decrease of free IL-18.

IL-18 binding protein (IL-18BP) is a circulating antagonist of the proinflammatory Th1 cytokine IL-18. It effectively blocks IL-18 by forming a 1:1 high affinity (Kd=400 pM) complex, exhibiting a very low dissociation rate. We have developed a sandwich ELISA for IL-18BPa and determined its limit of detection (62 pg/ml). Interference by IL-18 and related cytokines, as well as cross reactivity with other IL-18BP isoforms (b, c, and d) were determined. Using this ELISA, we measured serum IL-18BPa in large cohorts of healthy individuals and in septic patients. Serum IL-18BPa in healthy individuals was 2.15+/-0.15 ng/ml (range 0.5-7 ng/ml). In sepsis, the level rose to 21.9+/-1.44 ng/ml (range 4-132 ng/ml). Total IL-18 was measured in the same sera by an electrochemiluminescence assay and free IL-18 was calculated based on the mass action law. Total IL-18 was low in healthy individuals (64+/-17 pg/ml) and most of it ( approximately 85%) was in its free form. Total IL-18 and IL-18BPa were both elevated in sepsis patients upon admission (1.5+/-0.4 ng/ml and 28.6+/-4.5 ng/ml, respectively). At these levels, most of the IL-18 is bound to IL-18BPa, however the remaining free IL-18 is still higher than in healthy individuals. We conclude that IL-18BPa considerably inhibits circulating IL-18 in sepsis. Yet, exogenous administration of IL-18BPa may further reduce circulating IL-18 activity.

Alternative Splicing↗

Site-specific mutations in the mature form of human IL-18 with enhanced biological activity and decreased neutralization by IL-18 binding protein.

IL-18 can be considered a proinflammatory cytokine mediating disease as well as an immunostimulatory cytokine that is important for host defense against infection and cancer. The high-affinity, constitutively expressed, and circulating IL-18 binding protein (IL-18BP), which competes with cell surface receptors for IL-18 and neutralizes IL-18 activity, may act as a natural antiinflammatory as well as immunosuppressive molecule. In the present studies, the IL-18 precursor caspase-1 cleavage site was changed to a factor Xa site, and, after expression in Escherichia coli, mature IL-18 was generated by factor Xa cleavage. Mature IL-18 generated by factor Xa cleavage was fully active. Single point mutations in the mature IL-18 peptide were made, and the biological activities of the wild-type (WT) IL-18 were compared with those of the mutants. Mutants E42A and K89A exhibited 2-fold increased activity compared with WT IL-18. A double mutant, E42A plus K89A, exhibited 4-fold greater activity. Unexpectedly, IL-18BP failed to neutralize the double mutant E42A plus K89A compared with WT IL-18. The K89A mutant was intermediate in being neutralized by IL-18BP, whereas neutralization of the E42A mutant was comparable to that in the WT IL-18. The identification of E42 and K89 in the mature IL-18 peptide is consistent with previous modeling studies of IL-18 binding to IL-18BP and explains the unusually high affinity of IL-18BP for IL-18.

Cells, Cultured↗

Interleukin-18 binding protein in acute graft versus host disease and engraftment following allogeneic peripheral blood stem cell transplants.

Dysregulation of the cytokine network plays an important role in graft-versus-host disease (GVHD). Interleukin-18 (IL-18) is an obligatory cytokine for interferon-gamma (IFN-gamma) production and IFN-gamma and sIFN-gammaR are elevated in patients with GVHD. Because IL-18 binding protein (IL-18BP) is an inhibitor of IL-18-mediated IFN-gamma production, we evaluated IL-18BP levels in patients undergoing allogeneic peripheral blood stem cell transplantation (PBSCT). IL-18BP levels were assessed in 14 patients on day -10 (before conditioning), on the day of transplant, on the day of engraftment, and during transplant-related complications. A comparison of the kinetics of IL-18BP and soluble(s) IL-6R, sIFN-gammaR, IL-18 serum levels was performed. IL-18BP levels were assessed by specific monoclonal antibodies in a double-sandwich enzyme-linked immunosorbent assay (ELISA). In all patients IL-18BP levels decreased during conditioning and increased in parallel with engraftment (p < 0.05). Accordingly, during rejection, IL-18BP serum levels remained low and similar to pretransplant levels. The mean elevation of IL-18BP detected in association to acute GVHD was significantly higher in comparison to normal engraftment (p < 0.05). A correlation between IL-18BP, sIFNgammaR, and sIL-6R serum levels was found in all patients. No correlation between IL-18 and IL-18BP serum levels was found in patients undergoing uneventful PBSCT and rejection, whereas a marked increase in both IL-18 and IL-18BP levels was detected during acute GVHD (p < 0.01). Our data suggest that the dysregulation of IL-18 and IL-18BP may be important in the pathophysiology of transplant-related complications. Furthermore, because preliminary data from our group show that IL-18 blockage ameliorates GVHD in murine models, it is inferred that these cytokines may represent potential targets in the development of new therapeutic strategies in acute GVHD.

Acute Disease↗

Differential roles of interleukin-18 (IL-18) and IL12 for induction of gamma interferon by staphylococcal cell wall components and superantigens.

The roles of endogenous cytokines induced by either intact staphylococcal microorganisms or staphylococcal exotoxins were examined using human whole-blood cultures. To accomplish this, interleukin-18 binding protein (IL-18BP) and tumor necrosis factor binding protein (TNFbp) were used to neutralize IL-18 and TNF, respectively, whereas an anti-IL-12 monoclonal antibody was used to neutralize IL-12 and the IL-1 receptor antagonist (IL-1Ra) was used to block IL-1 receptors. Heat-killed Staphylococcus epidermidis and Staphylococcus aureus, as well as the staphylococcal superantigens toxic shock syndrome toxin-1 (TSST-1) and staphylococcus enterotoxin B (SEB) induced gamma interferon (IFN-gamma) production. Staphylococcus spp.-induced production of IFN-gamma required the presence of endogenous IL-18, IL-12, and TNF. In contrast, TSST-1-induced IFN-gamma was not significantly reduced in the presence of IL-18BP, anti-IL-12 antibodies, IL-1Ra, or anti-TNFbp. SEB-induced IFN-gamma was significantly inhibited only by anti-IL-12 antibodies, indicating that endogenous IL-18, IL-1, and TNF are not required for SEB-induced IFN-gamma. In conclusion, the mechanisms of IFN-gamma stimulation by intact staphylococcal microorganisms and by exotoxins differ, and this is likely due to the different receptors which are triggered on the cell membranes. In contrast to its role in the interactions between staphylococci and host cells, IL-18 does not appear to play a major role in superantigen-induced IFN-gamma.

Antigens, Bacterial↗

"Voluntary" user fees in Buenos Aires hospitals: innovation or imposition?

Voluntary user fees in hospitals in Buenos Aires, which operate outside official controls, have not featured in other studies of health care in Argentina. After providing a historical overview of different hospital funding sources, the authors focus on the activity of cooperadoras--the organizations responsible for levying voluntary fees. Using detailed data from two case-study hospitals and more general financial sources, they assess the importance of these fees, identifying sharp variations between different hospitals, serious problems of under-reporting, and potential abuses. The authors also examine the means by which fees are levied and the degree of coercion involved. Voluntary fees are not a particularly successful funding strategy: the income they generate is variable; they are almost entirely unregulated; and they sometimes conflict with other, more legitimate funding sources. Most importantly, their voluntaristic aspect is largely notional: most patients are heavily pressured to make payments. The main motivation for continuing with voluntary fees is to avoid the political fallout that would probably result from introduction of a formal user fees policy.

Argentina↗

IL-18 binding protein increases spontaneous and IL-1-induced prostaglandin production via inhibition of IFN-gamma.

IL-18 shares with IL-1 the same family of receptors and several identical signal transduction pathways. Because of these similarities, IL-18 was investigated for its ability to induce prostaglandin E(2) (PGE(2)) synthesis in human peripheral blood mononuclear cells (PBMC), a prominent, proinflammatory property of IL-1. IL-18 was highly active in PBMC by inducing the synthesis of the chemokine IL-8; however, no induction of PGE(2) synthesis nor cyclooxygenase type-2 gene expression was observed in PBMC stimulated with IL-18. In the same cultures, IL-1beta induced a 12-fold increase in PGE(2). Although IL-1beta-induced IL-8 synthesis was augmented 3-fold by IL-18, IL-18 suppressed IL-1beta-induced PGE(2) production by 40%. The suppressive effect of IL-18 on PGE(2) production was mediated by interferon (IFN)-gamma because anti-human IFN-gamma-antibody prevented IL-18-induced reduction in PGE(2). Consistent with these observations, IL-12, a known inducer of IFN-gamma, augmented IL-1beta-induced IFN-gamma but suppressed IL-1beta-induced PGE(2) by 75%. IL-18 binding protein (IL-18BP) is a naturally occurring and specific inhibitor of IL-18. When recombinant IL-18BP was added to PBMC cultures, unexpectedly, spontaneous PGE(2) production increased. PGE(2) production was also increased by the addition of IL-18BP to PBMC stimulated with either IL-1beta or IL-12 and also in whole blood cultures stimulated with Staphylococcus epidermidis. These studies demonstrate that IL-18BP decreases endogenous IL-18 activity by reducing IFN-gamma-mediated responses.

Cells, Cultured↗

Structural requirements of six naturally occurring isoforms of the IL-18 binding protein to inhibit IL-18.

A novel, constitutively expressed and secreted IL-18 binding protein (IL-18BP) neutralizes IL-18 and thereby suppresses the production of IFN-gamma, resulting in reduced T-helper type 1 immune responses. In the present study, four human and two mouse isoforms, resulting from mRNA splicing and found in various cDNA libraries, were expressed, purified, and assessed for binding and neutralization of IL-18 biological activities. Human IL-18BP isoform a (IL-18BPa) exhibited the greatest affinity for IL-18 with a rapid on-rate, a slow off-rate, and a dissociation constant (K(d)) of 399 pM. IL-18BPc shares the Ig domain of IL-18BPa except for the 29 C-terminal amino acids; the K(d) of IL-18BPc is 10-fold less (2.94 nM). Nevertheless, IL-18BPa and IL-18BPc neutralize IL-18 >95% at a molar excess of two. IL-18BPb and IL-18BPd isoforms lack a complete Ig domain and lack the ability to bind or neutralize IL-18. Murine IL-18BPc and IL-18BPd isoforms, possessing the identical Ig domain, also neutralize >95% murine IL-18 at a molar excess of two. However, murine IL-18BPd, which shares a common C-terminal motif with human IL-18BPa, also neutralizes human IL-18. Molecular modeling identified a large mixed electrostatic and hydrophobic binding site in the Ig domain of IL-18BP, which could account for its high affinity binding to the ligand. It is likely that preferential secretion of functional and nonfunctional isoforms of IL-18BP affect the immune response.

Amino Acid Sequence↗