RESUMEN
Targeted protein degradation via small-molecule modulation of cereblon offers vast potential for the development of new therapeutics. Cereblon-binding therapeutics carry the safety risks of thalidomide, which caused an epidemic of severe birth defects characterized by forelimb shortening or phocomelia. Here we show that thalidomide is not teratogenic in transgenic mice expressing human cereblon, indicating that binding to cereblon is not sufficient to cause birth defects. Instead, we identify SALL4 as a thalidomide-dependent cereblon neosubstrate. Human mutations in SALL4 cause Duane-radial ray, IVIC, and acro-renal-ocular syndromes with overlapping clinical presentations to thalidomide embryopathy, including phocomelia. SALL4 is degraded in rabbits but not in resistant organisms such as mice because of SALL4 sequence variations. This work expands the scope of cereblon neosubstrate activity within the formerly 'undruggable' C2H2 zinc finger family and offers a path toward safer therapeutics through an improved understanding of the molecular basis of thalidomide-induced teratogenicity.
Asunto(s)
Regulación de la Expresión Génica , Péptido Hidrolasas/química , Teratógenos/química , Talidomida/química , Factores de Transcripción/química , Proteínas Adaptadoras Transductoras de Señales , Animales , Proteínas de Unión al ADN/química , Proteínas de Unión al ADN/genética , Homocigoto , Humanos , Inmunohistoquímica , Células Madre Pluripotentes Inducidas , Ligandos , Masculino , Ratones , Ratones Transgénicos , Mutación , Proteínas del Tejido Nervioso/química , Proteínas del Tejido Nervioso/genética , Péptido Hidrolasas/genética , Proteolisis , Conejos , Testículo/metabolismo , Factores de Transcripción/genética , Ubiquitina-Proteína Ligasas/metabolismo , Dedos de ZincRESUMEN
Genome-wide association studies (GWAS) have identified loci reproducibly associated with pulmonary diseases; however, the molecular mechanism underlying these associations are largely unknown. The objectives of this study were to discover genetic variants affecting gene expression in human lung tissue, to refine susceptibility loci for asthma identified in GWAS studies, and to use the genetics of gene expression and network analyses to find key molecular drivers of asthma. We performed a genome-wide search for expression quantitative trait loci (eQTL) in 1,111 human lung samples. The lung eQTL dataset was then used to inform asthma genetic studies reported in the literature. The top ranked lung eQTLs were integrated with the GWAS on asthma reported by the GABRIEL consortium to generate a Bayesian gene expression network for discovery of novel molecular pathways underpinning asthma. We detected 17,178 cis- and 593 trans- lung eQTLs, which can be used to explore the functional consequences of loci associated with lung diseases and traits. Some strong eQTLs are also asthma susceptibility loci. For example, rs3859192 on chr17q21 is robustly associated with the mRNA levels of GSDMA (P = 3.55 × 10(-151)). The genetic-gene expression network identified the SOCS3 pathway as one of the key drivers of asthma. The eQTLs and gene networks identified in this study are powerful tools for elucidating the causal mechanisms underlying pulmonary disease. This data resource offers much-needed support to pinpoint the causal genes and characterize the molecular function of gene variants associated with lung diseases.
Asunto(s)
Asma/genética , Estudio de Asociación del Genoma Completo , Sitios de Carácter Cuantitativo , Proteínas Supresoras de la Señalización de Citocinas , Asma/metabolismo , Teorema de Bayes , Regulación de la Expresión Génica , Redes Reguladoras de Genes , Predisposición Genética a la Enfermedad , Humanos , Polimorfismo de Nucleótido Simple , Proteína 3 Supresora de la Señalización de Citocinas , Proteínas Supresoras de la Señalización de Citocinas/genética , Proteínas Supresoras de la Señalización de Citocinas/metabolismoRESUMEN
BACKGROUND: Varicella-zoster virus (VZV)-specific cell-mediated immunity is important for protection against VZV disease. We studied the relationship between VZV cell-mediated immunity and age after varicella or VZV vaccination in healthy and human immunodeficiency virus (HIV)-infected individuals. METHODS: VZV responder cell frequency (RCF) determinations from 752 healthy and 200 HIV-infected subjects were used to identify group-specific regression curves on age. RESULTS: In healthy individuals with past varicella, VZV RCF peaked at 34 years of age. Similarly, VZV-RCF after varicella vaccine increased with age in subjects aged <1 to 43 years. In subjects aged 61-90 years, VZV RCF after zoster vaccine decreased with age. HIV-infected children had lower VZV RCF estimates than HIV-infected adults. In both groups, VZV RCF results were low and constant over age. Varicella vaccination of HIV-infected children with CD4 levels 20% generated VZV RCF values higher than wild-type infection and comparable to vaccine-induced responses of healthy children. CONCLUSIONS: In immunocompetent individuals with prior varicella, VZV RCF peaked in early adulthood. Administration of varicella vaccine to HIV-infected or uninfected individuals aged >5 years generated VZV RCF values similar to those of immunocompetent individuals with immunity induced by wild-type infection. A zoster vaccine increased the VZV RCF of elderly adults aged <75 years to values higher than peak values induced by wild-type infection.
Asunto(s)
Vacuna contra la Varicela/inmunología , Varicela/inmunología , Herpesvirus Humano 3/inmunología , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Linfocitos T CD4-Positivos/inmunología , Niño , Preescolar , Infecciones por VIH/inmunología , Humanos , Inmunidad Celular/inmunología , Lactante , Modelos Logísticos , Estudios Longitudinales , Persona de Mediana EdadRESUMEN
Many patients with multiple myeloma (MM) initially respond to treatment with modern combination regimens including immunomodulatory agents (lenalidomide and pomalidomide) and proteasome inhibitors. However, some patients lack an initial response to therapy (i.e., are refractory), and although the mean survival of MM patients has more than doubled in recent years, most patients will eventually relapse. To address this need, we explored the potential of novel cereblon E3 ligase modulators (CELMoDs) for the treatment of patients with relapsed or refractory multiple myeloma (RRMM). We found that optimization beyond potency of degradation, including degradation efficiency and kinetics, could provide efficacy in a lenalidomide-resistant setting. Guided by both phenotypic and protein degradation data, we describe a series of CELMoDs for the treatment of RRMM, culminating in the discovery of CC-92480, a novel protein degrader and the first CELMoD to enter clinical development that was specifically designed for efficient and rapid protein degradation kinetics.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Antineoplásicos/farmacología , Mieloma Múltiple/tratamiento farmacológico , Ubiquitina-Proteína Ligasas/metabolismo , Proteínas Adaptadoras Transductoras de Señales/antagonistas & inhibidores , Animales , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Femenino , Humanos , Concentración 50 Inhibidora , Ratones , Mieloma Múltiple/patología , Recurrencia , Estereoisomerismo , Insuficiencia del Tratamiento , Ubiquitina-Proteína Ligasas/antagonistas & inhibidores , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
This study aimed to test the utility of the ozone challenge model for profiling novel compounds designed to reduce airway inflammation. The authors used a randomized, double-dummy, double-blind, placebo-controlled 3-period crossover design alternating single orally inhaled doses of fluticasone propionate (inhaled corticosteroids, 2 mg), oral prednisolone (oral corticosteroids, 50 mg), or matched placebo. At a 2-week interval, 18 healthy ozone responders (>10% increase in sputum neutrophils) underwent a 3-hour ozone (250 ppb)/intermittent exercise challenge starting 1 hour after drug treatment. Airway inflammation was assessed at 2 hours (breath condensate) and 3 hours (induced sputum) after ozone challenge. Compared to placebo, pretreatment with inhaled corticosteroids or oral corticosteroids resulted in a significant reduction (mean [95% confidence interval]) of sputum neutrophils by 62% (35%, 77%) and 64% (39%, 79%) and of sputum supernatant myeloperoxidase by 55% (41%, 66%) and 42% (25%, 56%), respectively. The authors conclude that an optimized ozone challenge model (including ozone responders and ensuring adequate drug levels during exposure) may be useful for testing novel anti-inflammatory compounds in early development.
Asunto(s)
Pruebas de Provocación Bronquial/métodos , Evaluación de Medicamentos/métodos , Ozono , Administración por Inhalación , Administración Oral , Adulto , Androstadienos/administración & dosificación , Androstadienos/farmacología , Antiinflamatorios/administración & dosificación , Antiinflamatorios/farmacología , Estudios Cruzados , Método Doble Ciego , Femenino , Fluticasona , Humanos , Masculino , Modelos Biológicos , Prednisolona/administración & dosificación , Prednisolona/farmacología , Pruebas de Función Respiratoria , Esputo/citología , Esputo/metabolismoRESUMEN
BACKGROUND: Incidence and severity of herpes zoster (HZ) and postherpetic neuralgia increase with age, associated with age-related decrease in immunity to varicella-zoster virus (VZV). One dose of zoster vaccine (ZV) has demonstrated substantial protection against HZ; this study examined impact of a second dose of ZV. METHODS: Randomized, double-blind, multicenter study with 210 subjects ≥60 years old compared immunity and safety profiles after one and two doses of ZV, separated by 6 weeks, vs. placebo. Immunogenicity was evaluated using VZV interferon-gamma (IFN-γ) enzyme-linked immunospot (ELISPOT) assay and VZV glycoprotein enzyme-linked immunosorbent antibody (gpELISA) assay. Adverse experiences (AEs) were recorded on a standardized Vaccination Report Card. RESULTS: No serious vaccine-related AEs occurred. VZV IFN-γ ELISPOT geometric mean count (GMC) of spot-forming cells per 10(6) peripheral blood mononuclear cells increased in the ZV group from 16.9 prevaccination to 49.5 and 32.8 at 2 and 6 weeks postdose 1, respectively. Two weeks, 6 weeks and 6 months postdose 2, GMC was 44.3, 42.9, and 36.5, respectively. GMC in the placebo group did not change during the study. The peak ELISPOT response occurred â¼2 weeks after each ZV dose. The gpELISA geometric mean titers (GMTs) in the ZV group were higher than in the placebo group at 6 weeks after each dose. Correlation between the IFN-γ ELISPOT and gpELISA assays was poor. CONCLUSIONS: ZV was generally well-tolerated and immunogenic in adults ≥60 years old. A second dose of ZV was generally safe, but did not boost VZV-specific immunity beyond levels achieved postdose 1.
Asunto(s)
Vacuna contra el Herpes Zóster/efectos adversos , Vacuna contra el Herpes Zóster/inmunología , Vacunación/efectos adversos , Vacunación/métodos , Anciano , Anciano de 80 o más Años , Anticuerpos Antivirales/sangre , Método Doble Ciego , Ensayo de Inmunoadsorción Enzimática , Ensayo de Immunospot Ligado a Enzimas , Femenino , Vacuna contra el Herpes Zóster/administración & dosificación , Herpesvirus Humano 3/inmunología , Humanos , Interferón gamma/metabolismo , Masculino , Persona de Mediana Edad , Placebos/administración & dosificaciónRESUMEN
BACKGROUND: Several studies suggest that inhaled and oral corticosteroids repress systemic inflammation in chronic obstructive pulmonary disease (COPD). However, the cytokines that may respond to these medications are unclear. METHOD: We used data from 41 patients with a history of stable moderate COPD (average age 64 years) who were randomised to inhaled fluticasone (500 microg twice daily from a Diskus inhaler), oral prednisone (30 mg daily) or placebo for 2 weeks. Using a multiplexed array system, different serum cytokines that have been implicated in COPD pathogenesis were measured. RESULTS: We found that compared with placebo, inhaled fluticasone significantly reduced levels of soluble tumour necrosis factor receptor-2 (sTNF-R2) by 24% (95% CI, 7-38%; p = 0.01), monocyte chemoattractant protein-1 by 20% (95% CI, 5-32%; p = 0.01), interferon gamma inducible CXCL10 (IP-10) by 43% (95% CI, 3-66%; p = 0.04), and soluble L-selectin levels by 15% (95% CI, 1-28%; p = 0.04). Compared with placebo, oral prednisone reduced levels of sTNF-R2 by 26% (95% CI, 15-36%; p < 0.001), L-selectin by 22% (95% CI, 8-34%; p = 0.004), intercellular adhesion molecule-1 by 31% (95% CI, 9-48%; p = 0.01), pulmonary and activation-regulated chemokine (PARC) by 18% (95% CI, 2-32%; p = 0.03) and IP-10 by 40% (95% CI, 0-64%; p = 0.05). sTNF-R2, L-selectin and IP-10 were significantly reduced by both oral and inhaled corticosteroids. The other cytokines were not significantly repressed by either oral or inhaled corticosteroids. CONCLUSIONS: In summary, inhaled and oral corticosteroids significantly repressed a selected number of systemic cytokines in patients with stable, moderate COPD; most of the steroid-responsive cytokines appear to be chemoattractants.
Asunto(s)
Androstadienos/administración & dosificación , Biomarcadores/sangre , Citocinas/sangre , Glucocorticoides/administración & dosificación , Enfermedad Pulmonar Obstructiva Crónica/sangre , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Administración por Inhalación , Administración Oral , Anciano , Femenino , Fluticasona , Humanos , Masculino , Persona de Mediana EdadRESUMEN
The objectives of this study were to determine the effect of single and repeat dosing with oral ondansetron, a 5-HT3-specific receptor blocker, on the degree and duration of bronchodilation induced by inhaled ipratropium bromide in patients with COPD. Five clinics and university medical centers in four countries participated in the study; 47 patients with COPD were randomized to treatment; 44 completed all treatments. Patients had a baseline (pre-bronchodilator) FEV1>1L and post-bronchodilator (200 mcg salbutamol) FEV1<90% of predicted, with FEV1 reversibility (to 80 mcg inhaled ipratropium bromide and 400 mcg salbutamol) of at least 12% or 200 mL over baseline. The study was divided into two parts. In Part A, each patient received in a random order, four-way crossover manner, single doses of ondansetron placebo (oral) plus ipratropium bromide placebo (inhaled), ondansetron placebo plus ipratropium bromide 40 mcg inhaled via MDI, ondansetron 24 mg oral plus ipratropium bromide placebo and ondansetron 24 mg plus ipratropium bromide 40 mcg. In Part B, each patient received in a random order, two-way crossover manner, ipratropium bromide 40 mcg tid via MDI plus ondansetron 8 mg oral, qid, for 2 days; on day 3 patients received a single dose of ipratropium bromide 40 mcg plus 8 mg oral ondansetron. Alternatively, patients received ipratropium bromide via MDI and oral ondansetron placebo, as described above. Statistically significant differences in weighted mean FEV1 (0-6h), peak FEV1 and FEV1 determined 6h post-dose were noted comparing ipratropium bromide to placebo. Similar positive results were observed for sGaw and FVC. Addition of ondansetron to ipratropium bromide did not significantly modify values obtained with ipratropium alone. Ipratropium bromide induced a marked bronchodilation, compared to placebo. Addition of ondansetron (single or repeated doses) did not significantly increase the degree or duration of bronchodilation induced by ipratropium alone. sGaw was consistently more sensitive than FEV1 in measuring extent and duration of bronchodilation.
Asunto(s)
Broncodilatadores/uso terapéutico , Ipratropio/uso terapéutico , Ondansetrón/uso terapéutico , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Antagonistas de la Serotonina/uso terapéutico , Administración por Inhalación , Administración Oral , Adulto , Anciano , Broncodilatadores/administración & dosificación , Estudios Cruzados , Método Doble Ciego , Esquema de Medicación , Quimioterapia Combinada , Femenino , Volumen Espiratorio Forzado , Humanos , Ipratropio/administración & dosificación , Masculino , Inhaladores de Dosis Medida , Persona de Mediana Edad , Ondansetrón/administración & dosificación , Antagonistas de la Serotonina/administración & dosificación , Capacidad VitalRESUMEN
Limited information exists regarding measurement, reproducibility and interrelationships of non-invasive biomarkers in smokers. We compared exhaled breath condensate (EBC) leukotriene B4 (LTB4) and 8-isoprostane, exhaled nitric oxide, induced sputum, spirometry, plethysmography, impulse oscillometry and methacholine reactivity in 18 smokers and 10 non-smokers. We assessed the relationships between these measurements and within-subject reproducibility of EBC biomarkers in smokers. Compared to non-smokers, smokers had significantly lower MMEF % predicted (mean 64.1 vs 77.7, p = 0.003), FEV1/FVC (mean 76.2 vs 79.8 p = 0.05), specific conductance (geometric mean 1.2 vs 1.6, p = 0.02), higher resonant frequency (mean 15.5 vs 9.9, p = 0.01) and higher EBC 8-isoprostane (geometric mean 49.9 vs 8.9 pg/ml p = 0.001). Median EBC pH values were similar, but a subgroup of smokers had airway acidification (pH < 7.2) not observed in non-smokers. Smokers had predominant sputum neutrophilia (mean 68.5%). Repeated EBC measurements showed no significant differences between group means, but Bland Altman analysis showed large individual variability. EBC 8-isoprostane correlated with EBC LTB4 (r = 0.78, p = 0.0001). Sputum supernatant IL-8 correlated with total neutrophil count per gram of sputum (r = 0.52, p = 0.04) and with EBC pH (r = -0.59, p = 0.02). In conclusion, smokers had evidence of small airway dysfunction, increased airway resistance, reduced lung compliance, airway neutrophilia and oxidative stress.
Asunto(s)
Fumar/metabolismo , Fumar/fisiopatología , Adulto , Biomarcadores/metabolismo , Pruebas de Provocación Bronquial , Estudios de Casos y Controles , Dinoprost/análogos & derivados , Dinoprost/metabolismo , Femenino , Humanos , Leucotrieno B4/metabolismo , Masculino , Persona de Mediana Edad , Óxido Nítrico/metabolismo , Intercambio Gaseoso Pulmonar/fisiología , Reproducibilidad de los Resultados , Capacidad Pulmonar Total/fisiologíaRESUMEN
To define the phenotypic characteristics and kinetics of T cell responses to a shingles vaccine in elderly individuals, 20 subjects > or =60 years of age received two doses of vaccine or placebo 6 weeks apart. VZV-specific T cell phenotypes and intracellular cytokines were determined by flow cytometry on blood mononuclear cells obtained pre-vaccination and up to 6 months after the second immunization. Results were compared with responses of five unvaccinated young adults. Pre-vaccination, elderly individuals had significantly lower VZV-specific effectors and cytokine-producing T cells compared with young adults. The vaccine significantly increased VZV-specific Th1, memory, early effector, and cutaneous homing receptor-bearing T cells.
Asunto(s)
Vacuna contra el Herpes Zóster/inmunología , Subgrupos de Linfocitos T/inmunología , Linfocitos T/inmunología , Factores de Edad , Anciano , Anciano de 80 o más Años , Citocinas/análisis , Femenino , Citometría de Flujo , Vacuna contra el Herpes Zóster/administración & dosificación , Humanos , Inmunización Secundaria , Leucocitos Mononucleares/química , Leucocitos Mononucleares/inmunología , Masculino , Vacunas Atenuadas/administración & dosificación , Vacunas Atenuadas/inmunologíaRESUMEN
BACKGROUND: Chronic obstructive pulmonary disease (COPD) is an inflammatory lung disease associated with significant systemic consequences. Recognition of the systemic manifestations has stimulated interest in identifying circulating biomarkers in these patients. A systematic analysis was undertaken of multiple protein analytes in the serum of well characterised patients with COPD and matched controls using novel protein microarray platform (PMP) technology. METHODS: Forty-eight patients (65% men) with COPD (forced expiratory volume in 1 s <55%) and 48 matched controls were studied. Anthropometric parameters, pulmonary function tests, 6-minute walk distance, the BODE index and the number of exacerbations were measured and the association of these outcomes with the baseline levels of 143 serum biomarkers measured by PMP was explored. RESULTS: Thirty biomarker clusters were identified and ranked by computing the predictive value of each cluster for COPD (partial least squares discriminant analysis). From the 19 best predictive clusters, 2-3 biomarkers were selected based on their pathophysiological profile (chemoattractants, inflammation, tissue destruction and repair) and the statistical significance of their relationship with clinically important end points was tested. The selected panel of 24 biomarkers correlated (p<0.01) with forced expiratory volume in 1 s, carbon monoxide transfer factor, 6-minute walk distance, BODE index and exacerbation frequency. CONCLUSION: PMP technology can be useful in identifying potential biomarkers in patients with COPD. Panels of selected serum markers are associated with important clinical predictors of outcome in these patients.
Asunto(s)
Biomarcadores/sangre , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Índice de Masa Corporal , Estudios de Casos y Controles , Femenino , Volumen Espiratorio Forzado/fisiología , Humanos , Masculino , Análisis por Micromatrices/métodos , Persona de Mediana Edad , Enfermedad Pulmonar Obstructiva Crónica/fisiopatologíaRESUMEN
RATIONALE: Smokers who develop chronic obstructive pulmonary disease (COPD) have amplified inflammation within their lungs, involving selective tissue accumulation of neutrophils, macrophages and CD8+ T cells. CD11b (Mac-1, alphaMbeta(2)-integrin) is both a complement receptor (CR3) and a cell adhesion molecule present on the surface of peripheral blood leukocytes, and undergoes rapid surface upregulation from preformed cytoplasmic stores on activation. Cellular activation can also trigger chemotaxis and shape change, the activation itself being caused by the binding of chemokines to cell surface receptors. METHODS: We developed a method of whole blood flow cytometry to measure neutrophil and monocyte CD11b upregulation on CD16+ and CD14+ cells, employing staining with the nuclear dye LDS-751 immediately before flow cytometry. In addition we assessed neutrophil shape change by modified gated autofluorescence with forward scatter (GAFS), this being correlated with chemotactic responses. RESULTS: In smokers with COPD there was a lower maximal shape change for neutrophils in response to CXCL8 (IL-8) in comparison to healthy smokers (p=0.025), and a trend for lower expression of CD11b and shape change in response to CXCL1 (GRO-alpha). Neutrophils were found to predominantly express chemokine receptors CXCR1 and CXCR2 and respond to CXCL8 with CD11b upregulation, while monocytes express more CCR2 and upregulate CD11b preferentially to CCL2 (MCP-1). A CXCR2 antagonist (SB-656933) was found to inhibit neutrophil CD11b upregulation (IC50=260.7nM) and shape change (IC50=310.5nM) in COPD patients. CONCLUSIONS: Neutrophils and monocytes participate in inflammatory processes in a range of diseases. These whole blood assays can be employed to monitor activity in disease and perform in vitro and ex vivo assessment of chemokine receptor (CXCR) antagonists.
Asunto(s)
Antígeno CD11b/análisis , Citometría de Flujo/métodos , Monocitos/inmunología , Neutrófilos/inmunología , Antígenos CD/análisis , Forma de la Célula , Quimiocina CXCL11 , Quimiocinas CXC/metabolismo , Relación Dosis-Respuesta a Droga , Proteínas Ligadas a GPI , Humanos , Interleucina-8/metabolismo , Receptores de Lipopolisacáridos/análisis , Monocitos/citología , Monocitos/metabolismo , Neutrófilos/citología , Neutrófilos/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/sangre , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Enfermedad Pulmonar Obstructiva Crónica/inmunología , Receptores de IgG/análisis , Receptores de Interleucina-8B/antagonistas & inhibidores , Receptores de Interleucina-8B/metabolismo , Reproducibilidad de los Resultados , Regulación hacia Arriba/efectos de los fármacosRESUMEN
IMPACT: This study explores the use of measuring plasma biomarkers at exacerbation of chronic obstructive pulmonary disease (COPD), providing insight into the underlying pathogenesis of these important events. RATIONALE: The use of measuring C-reactive protein (CRP) to confirm exacerbation, or to assess exacerbation severity, in COPD is unclear. Furthermore, it is not known whether there may be more useful systemic biomarkers. OBJECTIVE: To assess the use of plasma biomarkers in confirming exacerbation and predicting exacerbation severity. METHODS: We assessed 36 biomarkers in 90 paired baseline and exacerbation plasma samples from 90 patients with COPD. The diagnosis of exacerbation fulfilled both health care use and symptom-based criteria. Biomarker concentrations were related to clinical indices of exacerbation severity. Interrelationships between biomarkers were examined to gain information on mechanisms of systemic inflammation at exacerbation of COPD. MEASUREMENTS AND MAIN RESULTS: To confirm the diagnosis of exacerbation, the most selective biomarker was CRP. However, this was neither sufficiently sensitive nor specific alone (area under the receiver operating characteristic curve [AUC], 0.73; 95% confidence interval, 0.66-0.80). The combination of CRP with any one increased major exacerbation symptom recorded by the patient on that day (dyspnea, sputum volume, or sputum purulence) significantly increased the AUC to 0.88 (95% confidence interval, 0.82-0.93; p<0.0001). There were no significant relationships between biomarker concentrations and clinical indices of exacerbation severity. Interrelationships between biomarkers suggest that the acute-phase response is related, separately, to monocytic and lymphocytic-neutrophilic pathways. CONCLUSIONS: Plasma CRP concentration, in the presence of a major exacerbation symptom, is useful in the confirmation of COPD exacerbation. Systemic biomarkers were not helpful in predicting exacerbation severity. The acute-phase response at exacerbation was most strongly related to indices of monocyte function.
Asunto(s)
Biomarcadores/sangre , Proteína C-Reactiva/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/sangre , Anciano , Estudios de Seguimiento , Humanos , Pronóstico , Estudios Prospectivos , Índice de Severidad de la EnfermedadRESUMEN
A new manufacturing process, known as process upgrade varicella vaccine (PUVV) was developed for a refrigerated formulation of varicella vaccine and for an investigational zoster vaccine. Safety and tolerability of a two-dose regimen of high-titered (approximately 50,000 PFU) PUVV were compared to a lower-titer formulation (approximately 5400 PFU) of VARIVAX; in 1366 healthy subjects > or =13 years old. Only one vaccine-related clinical serious adverse experience (pruritus; no hospitalization) was reported, in the VARIVAX group. Injection-site adverse experiences following any dose were higher in the PUVV group, 70.0%, than in the VARIVAX group, 56.2%, but generally were mild. Immunogenicity were similar in both groups in seronegative subjects. PUVV was generally well tolerated, and elicited an immune response similar to that induced by the marketed formulation of VARIVAX.
Asunto(s)
Vacuna contra la Varicela/efectos adversos , Vacuna contra la Varicela/inmunología , Varicela/inmunología , Varicela/prevención & control , Herpes Zóster/inmunología , Herpes Zóster/prevención & control , Adolescente , Anticuerpos Antivirales/análisis , Anticuerpos Antivirales/biosíntesis , Formación de Anticuerpos/inmunología , Vacuna contra la Varicela/administración & dosificación , Método Doble Ciego , Femenino , Humanos , Inmunidad Celular/inmunología , Interferón gamma/biosíntesis , MasculinoRESUMEN
In vaccine clinical trials, humoral antibody responses are often used to measure the effect of a vaccine because they correlate with a vaccine's protective efficacy against the target disease. While the concept of a correlate of protection usually refers to establishing a protective level of antibody titre, identifying a clear-cut value is often impossible because vaccine efficacy is not related solely to the antibody titre. We propose examining the relationship between disease protection and the whole distribution of antibody responses rather than a single cut-off level. In particular, we use failure-time models to estimate the relationship between long-term disease breakthroughs and primary antibody responses after vaccination. We apply these models to show that the varicella antibody response measured by glycoprotein enzyme-linked immunosorbent assay 6 weeks after vaccination strongly correlate with protection against varicella (chickenpox); we used 7-year follow-up data from children who received one dose of a live attenuated varicella (Oka/Merck) vaccine. In addition, we explore the potential use of these models to predict long-term disease breakthrough rates and to estimate the predicted vaccine efficacy of a similar varicella vaccine made with a modified manufacturing process.
Asunto(s)
Anticuerpos Antivirales/biosíntesis , Varicela/inmunología , Herpesvirus Humano 3/inmunología , Modelos Inmunológicos , Modelos Estadísticos , Vacunación/métodos , Anticuerpos Antivirales/sangre , Varicela/prevención & control , Niño , Preescolar , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Lactante , Masculino , Estados Unidos , Vacunas de Productos Inactivados/inmunología , Vacunas de Productos Inactivados/normas , Vacunas Virales/inmunologíaRESUMEN
The majority of untreated human immunodeficiency virus (HIV) type 1-infected individuals ultimately develop uncontrolled viremia and progressive disease. Cytotoxic T lymphocytes (CTLs) are known to play an important role in controlling HIV-1 replication, which has led to an increasing interest in augmenting conventional antiretroviral therapy with therapeutic vaccination. The successful development of a therapeutic vaccine will rely on the ability to correlate an aspect of the immune response with clinical outcome. In this study, the CD8(+) T cell maturation status of antigen-specific cells in models of well and poorly controlled virus infections were compared, to show that a memory phenotype predominates when antigen loads are absent or low. In HIV-1 infection, the emergence of memory CD8(+) T cells was found to occur only in individuals with highly suppressed viral replication for an extended duration. Such assessments of the immune response may provide a refined measure of virus control.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Antígenos VIH/inmunología , Infecciones por VIH/inmunología , Infecciones por VIH/virología , VIH/inmunología , Inmunoterapia , Carga Viral , Fármacos Anti-VIH/uso terapéutico , Linfocitos T CD8-positivos/citología , Diferenciación Celular , Células Cultivadas , Femenino , Infecciones por VIH/tratamiento farmacológico , Humanos , Memoria Inmunológica , Subgrupos Linfocitarios/citología , Subgrupos Linfocitarios/inmunología , Masculino , Virus/inmunologíaRESUMEN
An interferon-gamma ELISPOT assay has been developed for assessment of cellular immune responses to Varicella-Zoster Virus (VZV) in large, multi-center clinical vaccine trials. We show that the assay performed best when testing peripheral blood mononuclear cells (PBMCs) that had been isolated and then frozen on the same day as blood was drawn, and that freezing PBMCs from blood that was stored overnight before processing resulted in dramatically reduced responses. This assay was used to monitor cell-mediated immunity (CMI) in response to a booster immunization with an investigational live, attenuated VZV vaccine in an elderly population that had been vaccinated 8-10 years previously. The booster vaccine elicited a 1.6- to 1.7-fold rise in the VZV-specific cellular immune response as measured by the ELISPOT assay. The increase from pre to post booster vaccination response was more pronounced (approximately 2.2-fold rise) in a subset of subjects who had received two prior immunizations with a live, attenuated vaccine.