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1.
J Clin Immunol ; 43(6): 1259-1271, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37036560

RESUMEN

PURPOSE: The FIGARO study aims to provide insights on real-world utilization and tolerability of facilitated subcutaneous immunoglobulin (fSCIG) for primary immunodeficiency disease (PID) or secondary immunodeficiency disease (SID). METHODS: This prospective, multicenter, observational study, evaluated medical records, charts, and diaries of patients who had received at least 1 fSCIG infusion for PID or SID. Data were analyzed by cohort (PID, SID) and age groups (pediatric [< 18 years], adult [18-64 years], older adult [≥ 65 years]). Patients were followed up to 36 months. RESULTS: The study enrolled 156 patients: 15 pediatric, 120 adult, 21 older-adult. Twelve-month follow-up data were available for 128 patients. fSCIG was mainly prescribed for PID among patients aged < 65 years and for SID among older adults. At inclusion, 75.6% received their fSCIG infusion at home, and 78.7% self-administered. Adults were more likely to receive their initial infusion at home and self-administer (81.7% and 86.6%, respectively) than pediatric patients (53.3% each) and older adults (57.1% and 52.4%, respectively). At 12 months, the proportion of patients infusing at home and self-administering increased to 85.8% and 88.2%. Regardless of age, most patients self-administered the full fSCIG dose at home every 3-4 weeks and required a single infusion site. The tolerability profile was consistent with previous pivotal trials. Acute severe bacterial infections occurred in 0%-9.1% of patients during follow-up visits (full cohort). CONCLUSIONS: FIGARO confirms the feasibility, tolerability, and good infection control of fSCIG in PID and SID patients across the age spectrum in both the home-setting and medical facility. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT03054181.


Asunto(s)
Síndromes de Inmunodeficiencia , Infecciones , Humanos , Niño , Anciano , Estudios Prospectivos , Inmunoglobulinas , Síndromes de Inmunodeficiencia/diagnóstico , Síndromes de Inmunodeficiencia/tratamiento farmacológico , Infusiones Subcutáneas , Infecciones/tratamiento farmacológico , Inmunoglobulinas Intravenosas/uso terapéutico
2.
Clin Immunol ; 198: 62-70, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-30389480

RESUMEN

The mechanism of the efficacy of Intravenous immunoglobulins (IVIG) in autoimmune and inflammatory diseases is not well understood. This study aimed at understanding mechanisms of IVIG-mediated suppression of effector cell activities of peripheral blood mononuclear cells (PBMC) in antibody-dependent cellular cytotoxicity (ADCC). We were particularly interested in CD56dim NK cells, the main ADCC effector cells in PBMC. Exposure of PBMC to IVIG for at least 48 h induced a caspase-3-dependent apoptotic cell death of CD56dim NK cells without affecting CD56bright NK cells. Induction of apoptosis in CD56dim NK cells and concomitant suppression of ADCC effector activities of PBMC was associated with the monomer fraction of IVIG. Moreover, it was independent of IgG sialyation, did not depend on engagement of FcγRIII and could not be mimicked by IVIG (Fab')2 or IVIG Fc preparations. The described effect could contribute to the reduction of peripheral NK cells observed during IVIG therapy in patients.


Asunto(s)
Citotoxicidad Celular Dependiente de Anticuerpos/efectos de los fármacos , Apoptosis/efectos de los fármacos , Antígeno CD56/análisis , Inmunoglobulinas Intravenosas/farmacología , Células Asesinas Naturales/efectos de los fármacos , Leucocitos Mononucleares/inmunología , Humanos , Células Asesinas Naturales/inmunología , Receptores de IgG/análisis
3.
J Neuroinflammation ; 12: 107, 2015 May 29.
Artículo en Inglés | MEDLINE | ID: mdl-26022648

RESUMEN

BACKGROUND: Schwann cells are the myelinating glial cells of the peripheral nervous system and exert important regenerative functions revealing them as central repair components of many peripheral nerve pathologies. Intravenous immunoglobulins (IVIG) are widely used to treat autoimmune and inflammatory diseases including immune-mediated neuropathies. Nevertheless, promotion of peripheral nerve regeneration is currently an unmet therapeutical goal. We therefore examined whether immunoglobulins affect glial cell homeostasis, differentiation, and Schwann cell dependent nerve regenerative processes. METHODS: The responses of different primary Schwann cell culture models to IVIG were investigated: immature or differentiation competent Schwann cells, myelinating neuron/glial cocultures, and dorsal root ganglion explants. Immature or differentiating Schwann cells were used to study cellular proliferation, morphology, and gene/protein expression. Myelination rates were determined using myelinating neuron/glia cocultures, whereas axonal outgrowth was assessed using non-myelinating dorsal root ganglion explants. RESULTS: We found that IVIG specifically bind to Schwann cells and detected CD64 Fc receptor expression on their surface. In response to IVIG binding, Schwann cells reduced proliferation rates and accelerated growth of cellular protrusions. Furthermore, we observed that IVIG treatment transiently boosts myelin gene expression and myelination-related signaling pathways of immature cells, whereas in differentiating Schwann cells, myelin expression is enhanced on a long-term scale. Importantly, myelin gene upregulation was not detected upon application of IgG1 control antibodies. In addition, we demonstrate for the first time that Schwann cells secrete interleukin-18 upon IVIG stimulation and that this cytokine instructs these cells to promote axonal growth. CONCLUSIONS: We conclude that IVIG can positively influence the Schwann cell differentiation process and that it enhances their regenerative potential.


Asunto(s)
Axones/efectos de los fármacos , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Inmunoglobulinas/farmacología , Células de Schwann , Animales , Animales Recién Nacidos , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Técnicas de Cocultivo , Humanos , Interleucina-18/farmacología , Ratones Endogámicos C57BL , Proteínas de la Mielina/genética , Proteínas de la Mielina/metabolismo , Neuroglía/fisiología , Neuronas/fisiología , Unión Proteica/efectos de los fármacos , Ratas , Ratas Wistar , Receptores de IgG/genética , Receptores de IgG/metabolismo , Células de Schwann/citología , Células de Schwann/efectos de los fármacos , Células de Schwann/fisiología , Nervio Ciático/citología , Transducción de Señal/efectos de los fármacos
4.
Blood ; 119(17): 4073-82, 2012 Apr 26.
Artículo en Inglés | MEDLINE | ID: mdl-22394599

RESUMEN

Today it is generally accepted that B cells require cognate interactions with CD4(+) T cells to develop high-affinity antibodies against proteins. CD4(+) T cells recognize peptides (epitopes) presented by MHC class II molecules that are expressed on antigen-presenting cells. Structural features of both the MHC class II molecule and the peptide determine the specificity of CD4(+) T cells that can bind to the MHC class II-peptide complex. We used a new humanized hemophilic mouse model to identify FVIII peptides presented by HLA-DRB1*1501. This model carries a knockout of all murine MHC class II molecules and expresses a chimeric murine-human MHC class II complex that contains the peptide-binding sites of the human HLA-DRB1*1501. When mice were treated with human FVIII, the proportion of mice that developed antibodies depended on the application route of FVIII and the activation state of the innate immune system. We identified 8 FVIII peptide regions that contained CD4(+) T-cell epitopes presented by HLA-DRB1*1501 to CD4(+) T cells during immune responses against FVIII. CD4(+) T-cell responses after intravenous and subcutaneous application of FVIII involved the same immunodominant FVIII epitopes. Interestingly, most of the 8 peptide regions contained promiscuous epitopes that bound to several different HLA-DR proteins in in vitro binding assays.


Asunto(s)
Formación de Anticuerpos/inmunología , Linfocitos T CD4-Positivos/inmunología , Modelos Animales de Enfermedad , Epítopos de Linfocito T/inmunología , Factor VIII/administración & dosificación , Factor VIII/inmunología , Cadenas HLA-DRB1/inmunología , Hemofilia A/inmunología , Animales , Presentación de Antígeno , Linfocitos T CD4-Positivos/metabolismo , Células Dendríticas/citología , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Cadenas HLA-DRB1/metabolismo , Haplotipos/genética , Hemofilia A/metabolismo , Hemofilia A/patología , Humanos , Inyecciones Intravenosas , Inyecciones Subcutáneas , Masculino , Ratones , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo
5.
Blood ; 118(13): 3698-707, 2011 Sep 29.
Artículo en Inglés | MEDLINE | ID: mdl-21705497

RESUMEN

Replacement of the missing factor VIII (FVIII) is the current standard of care for patients with hemophilia A. However, the short half-life of FVIII makes frequent treatment necessary. Current efforts focus on the development of longer-acting FVIII concentrates by introducing chemical and genetic modifications to the protein. Any modification of the FVIII protein, however, risks increasing its immunogenic potential to induce neutralizing antibodies (FVIII inhibitors), and this is one of the major complications in current therapy. It would be highly desirable to identify candidates with a high risk for increased immunogenicity before entering clinical development to minimize the risk of exposing patients to such altered FVIII proteins. In the present study, we describe a transgenic mouse line that expresses a human F8 cDNA. This mouse is immunologically tolerant to therapeutic doses of native human FVIII but is able to mount an antibody response when challenged with a modified FVIII protein that possesses altered immunogenic properties. In this situation, immunologic tolerance breaks down and antibodies develop that recognize both the modified and the native human FVIII. The applicability of this new model for preclinical immunogenicity assessment of new FVIII molecules and its potential use for basic research are discussed.


Asunto(s)
Factor VIII/genética , Factor VIII/inmunología , Hemofilia A/genética , Tolerancia Inmunológica/genética , Memoria Inmunológica/genética , Animales , Formación de Anticuerpos/genética , Formación de Anticuerpos/fisiología , Modelos Animales de Enfermedad , Factor VIII/antagonistas & inhibidores , Femenino , Hemofilia A/inmunología , Hemofilia A/patología , Humanos , Tolerancia Inmunológica/fisiología , Memoria Inmunológica/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Modelos Biológicos , Especificidad de la Especie
6.
Gut ; 60(8): 1050-9, 2011 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-21471573

RESUMEN

BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) has been linked to a loss of tolerance towards the resident microflora. Therapeutic use of probiotics is known to be strain specific, but precise mechanisms remain unclear. The role of NOD2 signalling and the protective effect of Lactobacillus peptidoglycan (PGN) and derived muropeptides in experimental colitis were evaluated. METHODS: The anti-inflammatory capacity of lactobacilli and derived bacterial compounds was evaluated using the 2,4,6-trinitrobenzene sulfonic acid (TNBS) colitis model. The role of NOD2, MyD88 and interleukin 10 (IL-10) in this protection was studied using Nod2(-/-), MyD88(-/-) and Il10-deficient mice, while induction of regulatory dendritic cells (DCs) was monitored through the expansion of CD103(+) DCs in mesenteric lymph nodes or after adoptive transfer of bone marrow-derived DCs. The development of regulatory T cells was investigated by following the expansion of CD4(+)FoxP3(+) cells. High-performance liquid chromatography and mass spectrometry were used to analyse the PGN structural differences. RESULTS: The protective capacity of strain Lactobacillus salivarius Ls33 was correlated with a local IL-10 production and was abolished in Nod2-deficient mice. PGN purified from Ls33 rescued mice from colitis in an IL-10-dependent manner and favoured the development of CD103(+) DCs and CD4(+)Foxp3(+) regulatory T cells. In vitro Ls33 PGN induced IL-10-producing DCs able to achieve in vivo protection after adoptive transfer in a NOD2-dependent way. This protection was also correlated with an upregulation of the indoleamine 2,3-dioxygenase immunosuppressive pathway. The protective capacity was not obtained with PGN purified from a non-anti-inflammatory strain. Structural analysis of PGNs highlighted in Ls33 the presence of an additional muropeptide, M-tri-Lys. The synthesised ligand protected mice from colitis in a NOD2-dependent but MyD88-independent manner. CONCLUSIONS: The results indicated that PGN and derived muropeptides are active compounds in probiotic functionality and might represent a useful therapeutic strategy in IBD.


Asunto(s)
Colitis/terapia , Inmunidad Celular , Lactobacillus , Proteína Adaptadora de Señalización NOD2/metabolismo , Peptidoglicano/uso terapéutico , Probióticos/uso terapéutico , Animales , Cromatografía Líquida de Alta Presión , Colitis/inmunología , Colitis/metabolismo , Células Dendríticas/inmunología , Modelos Animales de Enfermedad , Factores Inmunológicos/metabolismo , Interleucina-10/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Factor 88 de Diferenciación Mieloide/metabolismo , Linfocitos T Reguladores/inmunología
7.
Immunotherapy ; 14(2): 135-143, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34743590

RESUMEN

Aim: While facilitated subcutaneous immunoglobulin (fSCIG) has been evaluated in pediatric patients with primary immunodeficiency diseases in clinical trials, real-world data are lacking. Materials & methods: This multicenter, retrospective, chart review study assessed fSCIG utilization in 30 patients less than 18 years old, with primary or secondary immunodeficiency diseases. Medical records were reviewed at fSCIG initiation and at 6 months. Results: Most (90%) patients received their first fSCIG infusion at a medical facility; by 6 months, all fSCIG infusions were administered at home by the patient/caregiver, the majority infusing every 3-4 weeks into a single site. No serious adverse drug reactions occurred. Conclusion: This study supports the feasibility and tolerability of administering fSCIG at home to pediatric patients with immunodeficiencies. Clinical Trial Registration: DRKS00015436 (German Clinical Trials Register).


Asunto(s)
Inmunoglobulinas Intravenosas/uso terapéutico , Síndromes de Inmunodeficiencia/tratamiento farmacológico , Síndromes de Inmunodeficiencia/inmunología , Adolescente , Niño , Estudios de Factibilidad , Femenino , Humanos , Inmunoglobulinas Intravenosas/administración & dosificación , Inyecciones Subcutáneas , Masculino , Estudios Retrospectivos , Resultado del Tratamiento
8.
Expert Rev Clin Immunol ; 17(sup1): 7-8, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33908818

RESUMEN

Immunoglobulin replacement therapy has been shown in clinical trials to be an important therapeutic option for reducing the incidence of serious bacterial infections and improving the quality of life in patients with primary and secondary immunodeficiencies (PID and SID, respectively). This article summarizes a poster series presented at the 19th Biennial Meeting of the European Society for Immunodeficiencies (October 14-17, 2020) further evaluating real-world usage and patient/physician experience with Immune Globulin Subcutaneous (Human) 20% Solution (Ig20Gly) in patients with PID and facilitated subcutaneous immunoglobulin (fSCIG) in patients with PID or SID.

9.
J Clin Invest ; 116(12): 3160-70, 2006 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-17111046

RESUMEN

Control of pathogens by formation of abscesses and granulomas is a major strategy of the innate immune system, especially when effector mechanisms of adaptive immunity are insufficient. We show in human listeriosis that DCs expressing indoleamine 2,3-dioxygenase (IDO), together with macrophages, are major cellular components of suppurative granulomas in vivo. Induction of IDO by DCs is a cell-autonomous response to Listeria monocytogenes infection and was also observed in other granulomatous infections with intracellular bacteria, such as Bartonella henselae. Reporting on our use of the clinically applied anti-TNF-alpha antibody infliximab, we further demonstrate in vitro that IDO induction is TNF-alpha dependent. Repression of IDO therefore might result in exacerbation of granulomatous diseases observed during anti-TNF-alpha therapy. These findings place IDO(+) DCs not only at the intersection of innate and adaptive immunity but also at the forefront of bacterial containment in granulomatous infections.


Asunto(s)
Células Dendríticas/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenasa/genética , Listeria monocytogenes/crecimiento & desarrollo , Antígenos CD/análisis , Antígenos de Diferenciación Mielomonocítica/análisis , Complejo CD3/análisis , Células Cultivadas , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/metabolismo , Células Dendríticas/citología , Células Dendríticas/microbiología , Ensayo de Inmunoadsorción Enzimática , Expresión Génica/genética , Granuloma/genética , Granuloma/metabolismo , Granuloma/microbiología , Humanos , Immunoblotting , Inmunohistoquímica , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Interferón gamma/genética , Interferón gamma/metabolismo , Antígeno Lewis X/análisis , Listeriosis/genética , Listeriosis/metabolismo , Listeriosis/microbiología , Macrófagos/citología , Macrófagos/metabolismo , Macrófagos/microbiología , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Proteínas S100/análisis , Factores de Tiempo , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo
10.
J Neurosci Res ; 86(7): 1434-47, 2008 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-18061944

RESUMEN

Classical immunology textbooks have described the central nervous system as an immune-privileged site, i.e., as devoid of inflammatory and host-vs.-graft immunoreactions. This view has been refined, since we now know that hematopoietic cells infiltrate the CNS under certain circumstances and that CNS-resident cells are capable of launching an innate immune response. Microglia cells express an extensive repertoire of pattern-recognition receptors and act as sentinels surveilling the CNS for possible damage or infection. Astrocytes are the most abundant cell type in the brain, and they are capable of launching a strong supportive innate immune response. Novel findings show that both astrocytes and, surprisingly, even neurons express pattern-recognition receptors. Activation of these receptors leads to a functional response, indicating that cells other than microglia are capable of initiating a primary innate immune response against CNS-invading pathogens. Here, we put these findings into context with what has been learned from recent in vitro and in vivo experiments about the initiation of an innate immune response in the brain.


Asunto(s)
Encéfalo/inmunología , Enfermedades del Sistema Nervioso Central/inmunología , Animales , Encéfalo/microbiología , Encéfalo/patología , Enfermedades del Sistema Nervioso Central/genética , Enfermedades del Sistema Nervioso Central/microbiología , Humanos , Inmunidad Activa , Modelos Biológicos , Neuroglía/fisiología , Neuronas/fisiología , Transducción de Señal/fisiología , Receptores Toll-Like/análisis
11.
Immunobiology ; 213(8): 621-7, 2008.
Artículo en Inglés | MEDLINE | ID: mdl-18950592

RESUMEN

The toll-like receptor 4 Asp(299)Gly polymorphism results in an inactive receptor. Heterozygosis is associated with reduced LPS-inducible IL-10 protein and IL-10 mRNA from blood leukocytes and isolated monocytes, while numerous other mediators are not affected. We could exclude that this effect is due to the differences in the kinetics of IL-10 release, in the expression of total surface TLR4 or in LPS-binding to monocytes between subjects heterozygous for the Asp(299)Gly polymorphism or homozygous carriers of the wild-type allele. Furthermore, we could show that IL-10 induction in general requires stronger LPS-triggering than TNF and is more sensitive to LPS inhibitors. The lower number of responsive wild-type TLR4 receptors on monocytes of heterozygotes may explain why only IL-10 release is affected.


Asunto(s)
Interleucina-10/genética , Leucocitos Mononucleares/metabolismo , Lipopolisacáridos/metabolismo , Receptor Toll-Like 4/genética , Factor de Necrosis Tumoral alfa/metabolismo , Alelos , Genotipo , Heterocigoto , Homocigoto , Humanos , Inmunidad Innata , Interleucina-10/metabolismo , Leucocitos Mononucleares/citología , Lipopolisacáridos/inmunología , Polimorfismo de Nucleótido Simple , ARN Mensajero/análisis , Transducción de Señal/inmunología , Receptor Toll-Like 4/inmunología , Receptor Toll-Like 4/metabolismo , Factor de Necrosis Tumoral alfa/inmunología
12.
Immunobiology ; 213(3-4): 285-96, 2008.
Artículo en Inglés | MEDLINE | ID: mdl-18406374

RESUMEN

Despite similar clinical relevance of Gram-positive and Gram-negative infections, immune activation by Gram-positive bacteria is by far less well understood than immune activation by Gram-negative bacteria. Our group has made available highly purified lipoteichoic acids (LTA) as a key Gram-positive immunostimulatory component. We have characterized the reasons for lower potency of LTA compared to Gram-negative lipopolysaccharide (LPS), identifying lack of IL-12/IFNgamma induction as a general characteristic of TLR2 agonists, and need for presentation of LTA on surfaces for enhanced immunostimulatory potency, as major aspects. Aspects of chemokine induction, where LTA is more potent than LPS, have been addressed. Furthermore, novel complement and plant defence activation, as well as CD36 as a new LTA receptor, were identified. The bacterial costimuli and modulators of LTA inducible responses are being investigated: LTA isolated from so far 16 bacterial species, although different in structure, behave remarkably similar while whole live and killed bacteria differ with regard to the pattern of induced responses. The purification and characterization of the respective components of the bacterial cell wall has begun.


Asunto(s)
Citocinas/metabolismo , Bacterias Grampositivas/metabolismo , Inmunidad Innata , Lipopolisacáridos/metabolismo , Monocitos/microbiología , Animales , Bacterias/metabolismo , Antígenos CD36/biosíntesis , Pared Celular/metabolismo , Humanos , Interferón gamma/metabolismo , Interleucina-12/metabolismo , Interleucina-8/metabolismo , Ratones , Modelos Biológicos , Monocitos/metabolismo , Ácidos Teicoicos/metabolismo
13.
J Endotoxin Res ; 13(4): 199-218, 2007.
Artículo en Inglés | MEDLINE | ID: mdl-17956939

RESUMEN

The course of every infection is different. The same pathogen can lead to subclinical, mild, severe or lethal infections in individuals. But is this just chance or determined by individual differences--on the side of the host as well as on the side of the pathogen? If so, we might need to consider these variations for treatment decisions. Indeed, we now understand that genetic polymorphisms and health status represent inborn and acquired risk factors. Similarly, pathogens impress with an increasing number of already identified virulence factors and host response modifiers. The emerging, more complex, view of the factors determining course and outcome of infections promises to enable more tailored and thus, hopefully, more effective treatment decisions.


Asunto(s)
Infecciones Bacterianas/fisiopatología , Bacterias/clasificación , Bacterias/genética , Bacterias/patogenicidad , Infecciones Bacterianas/genética , Susceptibilidad a Enfermedades , Femenino , Humanos , Masculino , Factores de Riesgo , Virosis/genética , Virosis/fisiopatología , Virus/genética , Virus/patogenicidad
14.
J Endotoxin Res ; 12(3): 171-80, 2006.
Artículo en Inglés | MEDLINE | ID: mdl-16719988

RESUMEN

More than 90% of all publications on endotoxin were carried out with endotoxins (lipopolysaccharide, LPS) from enterobacteriaceae. We compared the immune stimulatory potency of 11 different LPSs using human whole blood incubations. While the majority of LPSs induced cytokine release equipotently, a 1,000-fold more LPS from Pseudomonas aeruginosa or Vibrio cholerae was still less potent in inducing TNF, IL-1 beta, IL-10 and IFN-gamma though it potently induced nanogram quantities IL-8. All LPSs tested, regardless of the micro-organism, showed Toll-like receptor (TLR)4-dependence, except for the LPSs from P. aeruginosa and V. cholerae, which were both TLR4- and TLR2-dependent. Interestingly, UV-inactivated P. aeruginosa bacteria, although Gram-negative, also showed TLR2- and TLR4-dependence. Re-purification of commercial LPS preparations by phenol re-extraction led to a complete loss of the TLR2 dependency, indicating contamination with lipoproteins. In the Limulus amebocyte lysate assay, often performed to exclude contamination in purified water likely to originate from P. aeruginosa, P. aeruginosa LPS was only 2-fold less potent than LPS from S. abortus equi or the assay standard LPS from E. coli. This results in an overestimation of pyrogenic burden by a factor of 500 in the sample when compared with the biological activity of highly purified P. aeruginosa LPS in human whole blood.


Asunto(s)
Toxinas Bacterianas/toxicidad , Leucocitos/efectos de los fármacos , Prueba de Limulus/métodos , Lipopolisacáridos/toxicidad , Animales , Sangre/efectos de los fármacos , Sangre/metabolismo , Células de la Médula Ósea/efectos de los fármacos , Células de la Médula Ósea/inmunología , Citocinas/metabolismo , Relación Dosis-Respuesta a Droga , Ensayo de Inmunoadsorción Enzimática , Escherichia coli/inmunología , Humanos , Leucocitos/inmunología , Leucocitos/metabolismo , Lipopolisacáridos/clasificación , Lipopolisacáridos/inmunología , Ratones , Ratones Endogámicos C3H , Ratones Noqueados , Pseudomonas aeruginosa/inmunología , Receptores Toll-Like/genética , Receptores Toll-Like/inmunología , Receptores Toll-Like/metabolismo
15.
J Endotoxin Res ; 12(2): 69-85, 2006.
Artículo en Inglés | MEDLINE | ID: mdl-16690010

RESUMEN

Muropeptides are breakdown products of peptidoglycan (PGN) of Gram-negative and Gram-positive bacteria. They are released during bacterial growth and division, as part of the host response by lysozyme and amidases, or upon antibiotic treatment. After phagocytosis of bacteria or bacterial breakdown products by host immune cells, the muropeptides trigger intracellular signaling cascades, leading to altered gene expression and activation of the immune response. Numerous muropeptides and derivatives have been synthesized chemically to characterize their immunostimulatory effects and adjuvant activity. Muramyl dipeptide, a natural partial structure of PGN, is the minimal structure with adjuvant activity. This review discusses the structure and occurrence of muropeptides and gives a broad overview of their inflammatory and adjuvant activity and the possible involvement of receptors in these responses.


Asunto(s)
Acetilmuramil-Alanil-Isoglutamina/análogos & derivados , Acetilmuramil-Alanil-Isoglutamina/toxicidad , Sistema Inmunológico/efectos de los fármacos , Animales , Sinergismo Farmacológico , Bacterias Grampositivas/química , Bacterias Grampositivas/metabolismo , Humanos , Péptidos/metabolismo , Relación Estructura-Actividad
16.
J Interferon Cytokine Res ; 26(12): 887-92, 2006 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-17238831

RESUMEN

Immune defense capacity differs between men and women. Whereas men are more prone to infection and sepsis, women more commonly develop autoimmune diseases. We investigated the difference in cytokine secretion between males and females in response to different immune stimuli. Whole blood from 154 healthy volunteers (age 24 +/- 5.2; 82 females, 72 males) was collected within 2 h on 2 consecutive days. Blood from males produced significantly more tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), IL-6, and IL-8 than blood from females in response to a high concentration of either lipopolysaccharide (LPS) or lipoteichoic acid (LTA), whereas IL-10 and interferon-gamma (IFN-gamma) secretion did not differ. Normalization of cytokine measurement to individual monocyte counts cancelled these differences for all parameters except TNF-alpha. Stimulation with a lower concentration of LPS (100 pg/mL) produced even stronger differences in cytokine release, which were not cancelled by normalization to the producing cells. The coefficients of variation (CV) of the LPS-induced and LTA-induced cytokine responses were higher in blood from women than men for all parameters and stimuli measured. Thus, the stronger innate immune response of males in comparison to females appears to stem not only from a difference in monocyte counts but also from the steepness of the response curve.


Asunto(s)
Citocinas/sangre , Inmunidad Innata/efectos de los fármacos , Lipopolisacáridos/farmacología , Ácidos Teicoicos/farmacología , Adulto , Células Sanguíneas/efectos de los fármacos , Células Sanguíneas/inmunología , Femenino , Humanos , Inmunidad Innata/inmunología , Masculino , Monocitos/efectos de los fármacos , Monocitos/inmunología , Factores Sexuales
17.
J Mol Med (Berl) ; 81(6): 368-72, 2003 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-12743710

RESUMEN

The recently described family of Toll-like receptors (TLRs) plays a major role in innate immunity by mediating inflammatory reactions against a wide array of pathogens. TLR-2 is reported to interact with various bacterial partial structures including lipoproteins, peptidoglycan, and lipoteichoic acid. Two polymorphisms of the TLR-2 gene have recently been described: Arg753Gln, correlated with the incidence of sepsis in a white population, and Arg677Trp, correlated with the incidence of lepromatous leprosy in an Asian population. Both polymorphisms, when inserted into expression vectors encoding for human TLR-2, reduced stimulation of Chinese hamster ovary cells by synthetic lipopeptides. We furthermore developed a rapid and inexpensive method for the detection of both single nucleotide polymorphisms based on restriction fragment length polymorphism. While no individuals carrying the Arg677Trp SNP were identified in a large group of whites, 9.4% of the study population were found to be heterozygous for the Arg753Gln polymorphism. This ratio is significantly higher than previously reported, and therefore detection of this polymorphism among patients may yield important information for the assessment of risk profiles regarding susceptibility to bacterial infections.


Asunto(s)
Frecuencia de los Genes/genética , Glicoproteínas de Membrana/genética , Reacción en Cadena de la Polimerasa/métodos , Polimorfismo de Nucleótido Simple , Receptores de Superficie Celular/genética , Alelos , Animales , Células CHO , Cricetinae , Cartilla de ADN , Femenino , Frecuencia de los Genes/inmunología , Genotipo , Humanos , Masculino , Glicoproteínas de Membrana/fisiología , Polimorfismo de Longitud del Fragmento de Restricción , Receptores de Superficie Celular/fisiología , Receptor Toll-Like 2 , Receptores Toll-Like
18.
J Immunol Methods ; 277(1-2): 53-63, 2003 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-12799039

RESUMEN

Recognition of pathogens by immune cells initiates the release of numerous signaling molecules, including cytokines and eicosanoids. Here, we describe a simple procedure by which eicosanoids such as prostaglandin E(2) (PGE(2)), leukotriene B(4) (LTB(4)) and thromboxane B(2) (TxB(2)) can be measured using commercial enzyme immunoassays (EIAs) in the supernatant of whole blood stimulated with inflammatory stimuli. This is illustrated for numerous stimuli. The kinetics by which lipopolysaccharide (LPS) induces cyclooxygenase (COX)-2 expression in this setup were determined by quantitative reverse transcription polymerase chain reaction (RT-PCR). The eicosanoid response of the blood of 160 healthy volunteers to 1 microg/ml LPS was measured. To determine whether the action of a drug in vivo is represented ex vivo in the eicosanoid response of blood, one volunteer took a standard dose of a number of commercially available cyclooxygenase inhibitors on different days and the eicosanoid response of his blood to LPS was determined before ingestion as well as 2 and 6 h afterwards. The efficacy of the different pharmaceuticals on cyclooxygenase but not lipoxygenase products or cytokines could be monitored ex vivo. Similarly, ex vivo eicosanoid release was measured in blood from 10 volunteers who had taken 50 mg flurbiprofen. The method described extends approaches for studying whole blood cytokine release to the lipid mediators formed from arachidonic acid. These important signaling molecules represent targets for pharmacological intervention, which can now be monitored in vitro, as well as ex vivo employing the same model. Furthermore, the assay could be used to characterize the immune status of patient groups or to monitor the course of disease.


Asunto(s)
Dinoprostona/sangre , Leucotrieno B4/sangre , Tromboxano B2/sangre , Adulto , Antiinflamatorios no Esteroideos/inmunología , Antiinflamatorios no Esteroideos/farmacología , Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa/farmacología , Dinoprostona/inmunología , Humanos , Técnicas para Inmunoenzimas , Inflamación/sangre , Inflamación/inmunología , Isoenzimas/genética , Isoenzimas/inmunología , Isoenzimas/metabolismo , Cinética , Leucotrieno B4/inmunología , Lipopolisacáridos/inmunología , Lipopolisacáridos/farmacología , Inhibidores de la Lipooxigenasa/farmacología , Masculino , Proteínas de la Membrana , Prostaglandina-Endoperóxido Sintasas/genética , Prostaglandina-Endoperóxido Sintasas/inmunología , Prostaglandina-Endoperóxido Sintasas/metabolismo , ARN Mensajero/química , ARN Mensajero/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Tromboxano B2/inmunología
19.
J Immunol Methods ; 275(1-2): 69-79, 2003 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-12667671

RESUMEN

Endotoxin (lipopolysaccharide, LPS) inducible cytokine release by human whole blood is increasingly used to model inflammatory responses in vitro, to detect the presence of pyrogenic contaminations as well as to monitor disease states or immunomodulatory treatments ex vivo. However, the LPS-stimulated blood model primarily allows the assessment of monocyte responses. Here, a whole blood model was established which allows assessment of lymphocyte responses. Four different superantigens, namely staphylococcal enterotoxin A and B (SEA, SEB), toxic shock syndrome toxin-1 (TSST-1) or streptococcal exotoxin A (SPEA) were tested with respect to the induction of lymphokine release. All superantigens were capable of inducing significant amounts of the lymphokines interferon-gamma (IFNgamma), interleukin 2 (IL-2), IL-4, IL-5, IL-13 and tumor necrosis factor beta (TNFbeta) after 72 h of incubation. Concentration-dependencies and kinetics were determined. Blood from 160 healthy donors was used to assess the variability of SEB-inducible lymphokine release. Interindividual differences were more pronounced compared to LPS-inducible monokine release. However, the individual response was maintained when blood from six donors was tested once a week for 8 weeks, suggesting that the individual response represents a donor characteristic. The model appears to be suitable for the evaluation of immunomodulatory agents in vitro as well as ex vivo.


Asunto(s)
Proteínas Bacterianas , Toxinas Bacterianas , Linfocinas/sangre , Linfocinas/metabolismo , Proteínas de la Membrana , Modelos Inmunológicos , Enterotoxinas/farmacología , Ensayo de Inmunoadsorción Enzimática , Exotoxinas/farmacología , Citometría de Flujo , Humanos , Técnicas In Vitro , Interferón gamma/sangre , Interferón gamma/metabolismo , Interleucinas/sangre , Interleucinas/metabolismo , Lipopolisacáridos/farmacología , Linfotoxina-alfa/sangre , Linfotoxina-alfa/metabolismo , Superantígenos/farmacología , Factor de Necrosis Tumoral alfa/metabolismo
20.
Immunobiology ; 209(8): 599-608, 2004.
Artículo en Inglés | MEDLINE | ID: mdl-15638128

RESUMEN

Activation of immune cells by Chlamydophila pneumoniae in vitro has been shown to be toll-like receptor (TLR2)-dependent, but TLR4 is also involved to a minor extent. To investigate the role of TLR2 and TLR4 in vivo, a murine model of C. pneumoniae infection was established. Mice were infected intranasally with a low inoculum of 106 C. pneumoniae elementary bodies (EB) and spreading of bacteria was monitored by real-time PCR. The bronchoalveolar lavage (BAL) showed maximal bacterial load on the day of infection and the lung 2 days later. By day 95, C. pneumoniae were eradicated completely. In serum, anti-C. pneumoniae IgG became detectable on day 18 by microimmunofluorescence test. The course of infection was mild with no apparent symptoms, lack of acute phase response and no induction of tumor necrosis factor-alpha and interleukin-6 in BAL, lung supernatants or blood. Infection of TLR2-/- and C3H/HeJ mice revealed no differences in clearance of bacteria and serological responses compared to wild-type controls, even if a dose of 10(7) EB was used. Intracellular replication of C. pneumoniae in the lungs was proven by the efficacy of antibiotic treatment. These findings indicate that in vivo TLR2 and TLR4 are not important for the development of antibodies and elimination of C. pneumoniae.


Asunto(s)
Infecciones por Chlamydophila/inmunología , Chlamydophila pneumoniae/inmunología , Glicoproteínas de Membrana/fisiología , Monocinas/metabolismo , Receptores de Superficie Celular/fisiología , Animales , Anticuerpos Antibacterianos/sangre , Azitromicina/farmacología , Azitromicina/uso terapéutico , Lavado Broncoalveolar , Infecciones por Chlamydophila/tratamiento farmacológico , Infecciones por Chlamydophila/genética , Chlamydophila pneumoniae/efectos de los fármacos , Chlamydophila pneumoniae/aislamiento & purificación , Femenino , Inmunidad Innata , Inmunoglobulina G/sangre , Inmunoglobulina M/sangre , Interleucina-6/análisis , Interleucina-6/metabolismo , Pulmón/microbiología , Glicoproteínas de Membrana/genética , Ratones , Ratones Endogámicos C3H , Ratones Mutantes , Mutación/genética , Receptores de Superficie Celular/genética , Rifampin/farmacología , Rifampin/uso terapéutico , Receptor Toll-Like 2 , Receptor Toll-Like 4 , Receptores Toll-Like , Factor de Necrosis Tumoral alfa/análisis , Factor de Necrosis Tumoral alfa/metabolismo
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