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1.
J Allergy Clin Immunol ; 130(1): 195-204.e9, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22521247

RESUMO

BACKGROUND: Newborns have frequent infections and manifest impaired vaccine responses, motivating a search for neonatal vaccine adjuvants. Alum is a neonatal adjuvant but might confer a T(H)2 bias. Toll-like receptor (TLR) agonists are candidate adjuvants, but human neonatal cord blood monocytes demonstrate impaired T(H)1-polarizing responses to many TLR agonists caused by plasma adenosine acting through cyclic AMP. TLR8 agonists, including imidazoquinolines (IMQs), such as the small synthetic 3M-002, induce adult-level TNF from neonatal monocytes, but the scope and mechanisms of IMQ-induced activation of neonatal monocytes and monocyte-derived dendritic cells (MoDCs) have not been reported. OBJECTIVE: We sought to characterize IMQ-induced activation of neonatal monocytes and MoDCs. METHODS: Neonatal cord and adult peripheral blood monocytes and MoDCs were cultured in autologous plasma; levels of alum- and TLR agonist-induced cytokines and costimulatory molecules were measured. TLR8 and inflammasome function were assayed by using small interfering RNA and Western blotting/caspase-1 inhibitory peptide, respectively. The ontogeny of TLR8 agonist-induced cytokine responses was defined in rhesus macaque whole blood ex vivo. RESULTS: IMQs were more potent and effective than alum at inducing TNF and IL-1ß from monocytes. 3M-002 induced robust TLR pathway transcriptome activation and T(H)1-polarizing cytokine production in neonatal and adult monocytes and MoDCs, signaling through TLR8 in an adenosine/cyclic AMP-refractory manner. Newborn MoDCs displayed impaired LPS/ATP-induced caspase-1-mediated IL-1ß production but robust 3M-002-induced caspase-1-mediated inflammasome activation independent of exogenous ATP. TLR8 IMQs induced robust TNF and IL-1ß in whole blood of rhesus macaques at birth and infancy. CONCLUSIONS: IMQ TLR8 agonists engage adenosine-refractory TLR8 and inflammasome pathways to induce robust monocyte and MoDC activation and represent promising neonatal adjuvants.


Assuntos
Adenosina/metabolismo , Caspase 1/metabolismo , Células Dendríticas/imunologia , Imidazóis/farmacologia , Monócitos/imunologia , Quinolinas/farmacologia , Receptor 8 Toll-Like/agonistas , Adjuvantes Imunológicos , Adulto , Compostos de Alúmen , Animais , Citocinas/imunologia , Citocinas/metabolismo , Humanos , Recém-Nascido , Macaca mulatta
2.
J Pers Soc Psychol ; 95(6): 1252-67, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19025282

RESUMO

Collectivists know themselves better than individualists do, in that collectivists provide more accurate self-predictions of future behavior in situations with moral or altruistic overtones. In 3 studies, respondents from individualist cultures overestimated the likelihood that they would act generously in situations involving redistributing a reward (Study 1), donating money (Study 2), or avoiding rude behavior (Study 3), whereas collectivists were, in general, more accurate in their self-predictions. Both groups were roughly accurate in predicting the behavior of their peers. Collectivists were more accurate in their self-predictions than were individualists, even when both groups were sampled from the same cultural group (Study 4). Discussion centers on culturally specific motivations that may bias the accuracy of self-insight and social insight.


Assuntos
Cultura , Personalidade , Autoimagem , Adolescente , Comportamento Cooperativo , Comparação Transcultural , Feminino , Humanos , Masculino , Motivação , Fatores Socioeconômicos , Adulto Jovem
3.
Drug News Perspect ; 21(2): 69-87, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18389099

RESUMO

Imiquimod 5% cream is approved for the topical treatment of external anogenital warts caused by human papillomavirus (HPV) and for the skin cancer conditions superficial basal cell carcinoma and actinic keratosis. This drug is the first approved topically active Toll-like receptor (TLR) 7 agonist. Imiquimod activates innate immune cells to produce interferon-a and other cytokines. The induced cytokine cascade, in combination with effects in enhancing antigen presentation, also promotes an antigen-specific T helper type 1 cell-mediated immune response. This immune-based mechanism provides activity against a number of viruses and other intracellular pathogens. Imiquimod was effective topically in clinical studies for HPV but caused mixed results for Molluscum contagiosum, and herpes simplex virus (HSV). Activity against several other viruses were reported in case reports or patient series involving "off-label" usage of imiquimod, while others were evaluated only in preclinical models. Resiquimod, a more potent investigational analogue of imiquimod with mixed TLR7/8 agonist activity, was evaluated in clinical studies topically for the treatment of HSV and systemically for hepatitis C virus also with mixed success. This review focuses on the mechanism of action and antiviral usage reported for the TLR7 agonist imiquimod, the TLR7/8 agonist resiquimod and related imidazoquinoline analogues.


Assuntos
Antivirais/farmacologia , Viroses/tratamento farmacológico , Aminoquinolinas/farmacologia , Animais , Ensaios Clínicos como Assunto , Farmacorresistência Viral , Humanos , Imidazóis/farmacologia , Imiquimode , Receptor 7 Toll-Like/agonistas , Receptor 8 Toll-Like/agonistas
4.
Expert Rev Vaccines ; 6(5): 835-47, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17931162

RESUMO

Synthetic immune response modifiers, such as resiquimod, are Toll-like receptor 7 and 8 agonists that act as vaccine adjuvants, enhancing antigen-specific antibody production and skewing immunity towards a Th1 response. These compounds stimulate dendritic cells to secrete cytokines, upregulate costimulatory molecule expression and enhance antigen presentation to T cells. The compounds have demonstrated vaccine adjuvant properties in a number of animal models. The adjuvant effects can be enhanced by measures that allow the drug to stay localized with the vaccine without quickly entering the systemic circulation. Clinical studies demonstrate that topical application of resiquimod and analogs is safe and effective at activating the local immune response. For injection, resiquimod or a similar compound may need to be formulated to allow for local immune activation without induction of systemic cytokines.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Imidazóis/administração & dosagem , Fatores Imunológicos/administração & dosagem , Vacinas/administração & dosagem , Animais , Humanos , Imidazóis/imunologia , Fatores Imunológicos/imunologia , Vacinas/imunologia
5.
Cancer Res ; 67(4): 1823-31, 2007 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-17308125

RESUMO

Chronic activation through Toll-like receptors (TLR) occurs in a number of pathologic settings, but has not been studied to the same extent as primary activation. TLR7, expressed by B cells and some dendritic cells, recognizes molecular patterns associated with viruses that can be mimicked by synthetic imidazoquinolines. In response to primary stimulation with the imidazoquinoline, S28690, human mononuclear cells produced tumor necrosis factor-alpha, but were unable to do so upon restimulation with S28690. This state of "tolerization" lasted at least 5 days. Using chronic lymphocytic leukemia B cells as a model to facilitate biochemical analysis, the tolerized state was found to be associated with altered receptor components, including down-regulated expression of TLR7 mRNA and decreased levels of interleukin-1 receptor-associated kinase 1. Tolerization was characterized by a transcriptionally regulated block in stress-activated protein kinase and nuclear factor kappaB activation, with relatively preserved activation of extracellular signal-regulated kinase (ERK). Tolerized chronic lymphocytic leukemia cells were found to be more sensitive to cytotoxic chemotherapeutic agents, in part through altered stress-activated protein kinase signaling pathways. This property of the TLR7-tolerized state may potentially be exploited in the treatment of B cell cancers.


Assuntos
Linfócitos B/efeitos dos fármacos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Receptor 7 Toll-Like/fisiologia , Idoso , Idoso de 80 Anos ou mais , Linfócitos B/patologia , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Imidazóis/farmacologia , Quinases Associadas a Receptores de Interleucina-1/biossíntese , Leucemia Linfocítica Crônica de Células B/sangue , Leucemia Linfocítica Crônica de Células B/metabolismo , Leucemia Linfocítica Crônica de Células B/patologia , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Quinolinas/farmacologia , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Transdução de Sinais , Receptor 7 Toll-Like/agonistas , Receptor 7 Toll-Like/biossíntese , Transcrição Genética , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/genética , Vincristina/farmacologia
6.
J Transl Med ; 5: 7, 2007 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-17257431

RESUMO

BACKGROUND: The objective of this study was to identify the molecular processes responsible for the anti-lesional activity of imiquimod in subjects with actinic keratosis using global gene expression profiling. METHODS: A double-blind, placebo-controlled, randomized study was conducted to evaluate gene expression changes in actinic keratosis treated with imiquimod 5% cream. Male subjects (N = 17) with > or = 5 actinic keratosis on the scalp applied placebo cream or imiquimod 3 times a week on nonconsecutive days for 4 weeks. To elucidate the molecular processes involved in actinic keratosis lesion regression by imiquimod, gene expression analysis using oligonucleotide arrays and real time reverse transcriptase polymerase chain reaction were performed on shave biopsies of lesions taken before and after treatment. RESULTS: Imiquimod modulated the expression of a large number of genes important in both the innate and adaptive immune response, including increased expression of interferon-inducible genes with known antiviral, anti-proliferative and immune modulatory activity, as well as various Toll-like receptors. In addition, imiquimod increased the expression of genes associated with activation of macrophages, dendritic cells, cytotoxic T cells, and natural killer cells, as well as activation of apoptotic pathways. CONCLUSION: Data suggest that topical application of imiquimod stimulates cells in the skin to secrete cytokines and chemokines that lead to inflammatory cell influx into the lesions and subsequent apoptotic and immune cell-mediated destruction of lesions.


Assuntos
Aminoquinolinas/administração & dosagem , Aminoquinolinas/uso terapêutico , Ceratose Actínica/tratamento farmacológico , Ceratose Actínica/imunologia , Imunidade Adaptativa/efeitos dos fármacos , Imunidade Adaptativa/genética , Adjuvantes Imunológicos/farmacologia , Administração Tópica , Idoso , Idoso de 80 Anos ou mais , Apoptose/efeitos dos fármacos , Apoptose/genética , Proliferação de Células/efeitos dos fármacos , Quimiocinas/genética , Quimiocinas/metabolismo , Demografia , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Formas de Dosagem , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Imiquimode , Imunidade Inata/efeitos dos fármacos , Imunidade Inata/genética , Interferon Tipo I/farmacologia , Ceratose Actínica/genética , Ceratose Actínica/patologia , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Receptores de Reconhecimento de Padrão/metabolismo , Reprodutibilidade dos Testes , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/imunologia
7.
Antiviral Res ; 73(1): 1-11, 2007 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16959331

RESUMO

Toll-like receptors (TLR) detect conserved molecular patterns expressed by pathogens. Detection of the "molecular signature" for RNA viruses including influenza has been attributed to TLR3, TLR7, and TLR8. In the present study, compound 3M-011 was shown to be a synthetic human TLR7/8 agonist and cytokine inducer. 3M-011 was investigated as a stand-alone immune response modifier in a rat model of human influenza. Intranasal (IN) administration of 3M-011 significantly inhibited H3N2 influenza viral replication in the nasal cavity when administered from 72 h before IN viral inoculation to 6h after inoculation. Viral inhibition correlated with the ability of the TLR7/8 agonist to stimulate type I interferon (IFN) and other cytokines such as tumor necrosis factor-alpha, interleukin-12, and IFN-gamma from rat peripheral blood mononuclear cells. Prophylactic administration of TLR7/8 agonist also suppressed influenza viral titers in the lung, which corresponded with local IFN production. The activity of the TLR7/8 agonist resulted in greater inhibition of viral titers compared to rat recombinant IFN-alpha administered in a comparable dosing regimen. These studies indicate that TLR7/8 agonists may have prophylactic and therapeutic benefits in the treatment of respiratory viral infections, such as influenza, when administered prior to or shortly after viral inoculation.


Assuntos
Vírus da Influenza A Subtipo H3N2/patogenicidade , Influenza Humana/tratamento farmacológico , Influenza Humana/imunologia , Receptor 7 Toll-Like/agonistas , Receptor 8 Toll-Like/agonistas , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Imunidade Inata , Influenza Humana/virologia , Interferon Tipo I/metabolismo , Leucócitos Mononucleares/imunologia , Pulmão/virologia , Ratos , Ratos Endogâmicos F344 , Receptor 7 Toll-Like/administração & dosagem , Receptor 8 Toll-Like/administração & dosagem , Replicação Viral/efeitos dos fármacos
8.
Pediatrics ; 118(6): 2498-503, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17142536

RESUMO

OBJECTIVES: Inborn defects in Toll-like receptor signaling are recently described primary immunodeficiencies that predispose affected children to life-threatening infections. Patients with interleukin-1 receptor-associated kinase-4 deficiency are prone to invasive pneumococcal disease, and patients with UNC-93B deficiency are prone to herpes simplex virus encephalitis. These genetic disorders are underdiagnosed, partly because diagnosis currently requires expensive and time-consuming techniques available at only a few specialized centers worldwide. We, therefore, aimed to develop a cheap and fast test for the detection of defects in Toll-like receptor signaling. PATIENTS AND METHODS: We used flow cytometry to evaluate the cleavage of membrane-bound L-selectin on granulocytes in 38 healthy controls and in 7 patients with genetically defined Toll-like receptor signaling defects (5 patients with interleukin-1 receptor-associated kinase-4 deficiency and 2 patients with UNC-93B deficiency), on activation with various Toll-like receptor agonists. RESULTS: Impaired L-selectin shedding was observed with granulocytes from all of the interleukin-1 receptor-associated kinase-4-deficient patients on activation with agonists of Toll-like receptors 1/2, 2/6, 4, 7, and 8 and with granulocytes from all of the UNC-93B-deficient patients on activation with agonists of Toll-like receptors 7 and 8. All of the healthy controls responded to these stimuli. CONCLUSIONS: The assessment of membrane-bound L-selectin cleavage on granulocytes by flow cytometry may prove useful for the detection of primary immunodeficiencies in the Toll-like receptor pathway, such as interleukin-1 receptor-associated kinase-4 deficiency and UNC-93B deficiency. This procedure is cheap and rapid. It may, therefore, be suitable for routine testing worldwide in children with invasive pneumococcal disease and in patients with herpes simplex encephalitis.


Assuntos
Citometria de Fluxo , Quinases Associadas a Receptores de Interleucina-1/deficiência , Proteínas de Membrana Transportadoras/deficiência , Transdução de Sinais , Receptores Toll-Like/genética , Criança , Humanos , Fatores de Tempo
9.
Appl Opt ; 45(28): 7410-28, 2006 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-16983431

RESUMO

During the passage of a cold front in March 2002, bio-optical properties examined in coastal waters impacted by the Mississippi River indicated that westward advective flows and increasing river discharge containing high concentrations of nonalgal particles contributed significantly to surface optical variability. A comparison of seasonal data from three cruises indicated spectral models of absorption and scattering to be generally consistent with other coastal environments, while their parameterization in terms of chlorophyll (Chl) alpha concentration showed seasonal variability. The exponential slope of the colored dissolved organic matter (CDOM) averaged 0.0161+/-0.00054 nm(-1) and nonalgal absorption averaged 0.011 nm(-1) with deviations from general trends observed due to anomalous water properties. Although the phytoplankton specific absorption coefficients varied over a wide range [0.02 to 0.1 m2 (mg Chl)(-1) at 443 nm] being higher in offshore surface waters, values of phytoplankton absorption spectra at the Sea-Viewing Wide Field-of-View Sensor (SeaWiFS) wave bands were highly correlated to modeled values. Particulate scattering characteristics were similar to observations for other coastal waters, while backscattering ratios were on average lower in phytoplankton-dominated surface waters (0.011+/-0.003) and higher in low Chl near-bottom waters (0.0191+/-0.0045). Average percent differences in remote sensing reflectance Rrs derived from modeled and in-water radiometric measurements were highest in the blue wave bands (52%) and at locations with more stratified water columns. SeaWiFS estimates of Chl and CDOM absorption derived using regional empirical algorithms were highly correlated to in situ data.


Assuntos
Algoritmos , Colorimetria/métodos , Monitoramento Ambiental/métodos , Interpretação de Imagem Assistida por Computador/métodos , Rios/química , Poluentes Químicos da Água/química , Água/química , Cor , Luz , Estados Unidos
10.
Science ; 314(5797): 308-12, 2006 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-16973841

RESUMO

Herpes simplex virus-1 (HSV-1) encephalitis (HSE) is the most common form of sporadic viral encephalitis in western countries. Its pathogenesis remains unclear, as it affects otherwise healthy patients and only a small minority of HSV-1-infected individuals. Here, we elucidate a genetic etiology for HSE in two children with autosomal recessive deficiency in the intracellular protein UNC-93B, resulting in impaired cellular interferon-alpha/beta and -lambda antiviral responses. HSE can result from a single-gene immunodeficiency that does not compromise immunity to most pathogens, unlike most known primary immunodeficiencies. Other severe infectious diseases may also reflect monogenic disorders of immunity.


Assuntos
Encefalite por Herpes Simples/genética , Predisposição Genética para Doença , Herpesvirus Humano 1 , Interferons/biossíntese , Proteínas de Membrana Transportadoras/deficiência , Proteínas de Membrana Transportadoras/fisiologia , Pré-Escolar , Citocinas/biossíntese , Encefalite por Herpes Simples/imunologia , Feminino , Herpesvirus Humano 1/imunologia , Humanos , Lactente , Interferon-alfa/biossíntese , Interferon-alfa/imunologia , Interferon beta/biossíntese , Interferon beta/imunologia , Interferon gama/biossíntese , Interferon gama/imunologia , Interferons/imunologia , Leucócitos Mononucleares/imunologia , Masculino , Proteínas de Membrana Transportadoras/genética , Mutação , Linhagem , Transdução de Sinais , Receptor 3 Toll-Like/agonistas , Receptor 3 Toll-Like/fisiologia , Receptores Toll-Like/agonistas , Receptores Toll-Like/fisiologia
11.
J Biomol Screen ; 11(6): 575-85, 2006 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16760371

RESUMO

The authors describe an assay to quantitate DNA fragmentation using terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling (TUNEL) stain, adapted to a 96-well microplate format for adherent cells, and an automated high-content screening imager. The apoptotic responses to actinomycin D (a known antineoplastic agent) to imiquimod (a small-molecule toll-like receptor [TLR] 7 agonist used in skin cancer treatment) and to several structurally related TLR 7/8 agonists were evaluated in squamous carcinoma SCC15 and SCC25 cells and normal human keratinocytes. Potent proapoptotic and growth-impairing (as determined by reduced cell numbers) actions of actinomycin D (1-300 ng/mL) were discerned with the assay. Consistent with previous reports, imiquimod (at 300 microM; approximately 75 microg/mL) induced TUNEL positivity of malignant cell cultures, but this effect also occurred in normal keratinocytes. Two related TLR agonists induced apoptosis at lower concentrations. However, the concentrations of these and the imiquimod necessary to elicit cancer cell apoptosis were 300 to 1000 times higher relative to their ability to induce the secretion of an antineoplastic protein, interferon-alpha, from human blood monocytes. This TUNEL analysis allows the quantitative comparison of compounds' apoptotic activity toward adherent malignant and normal cells and may be useful for hit characterization after a screen.


Assuntos
Aminoquinolinas/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma de Células Escamosas/patologia , Células Epiteliais/efeitos dos fármacos , Receptores Toll-Like/agonistas , Antineoplásicos/farmacologia , Apoptose/imunologia , Automação , Carcinoma de Células Escamosas/imunologia , Linhagem Celular , Técnicas Citológicas , Células Epiteliais/patologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Imiquimode , Queratinócitos/efeitos dos fármacos , Queratinócitos/patologia
12.
Blood ; 108(4): 1284-90, 2006 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-16638933

RESUMO

Newborns are prone to microbial infection and have poor memory responses to multiple antigens. We have previously shown that human neonatal blood monocytes exhibit impaired TNF-alpha responses to most known TLR agonists, including the pure TLR7 agonist imiquimod. Surprisingly, however, neonatal TNF-alpha responses to the imiquimod congener R-848 (TLR 7/8) were fully intact. We now show that TLR8 agonists, including R-848 (TLR7/8), the imidazoquinoline congeners 3M-003 (TLR7/8) and 3M-002 (TLR8), as well as single-stranded viral RNAs (TLR8) induced robust production of the Th1-polarizing cytokines TNF-alpha and IL-12 from neonatal antigen-presenting cells (APCs) that substantially exceeds responses induced by TLR-2, -4, or -7 (alone) agonists. TLR8 agonists also effectively induced up-regulation of the costimulatory molecule CD40 on neonatal and adult myeloid dendritic cells (DCs). The strong activity of TLR8 agonists correlates with their induction of p38 MAP kinase phosphorylation and with degradation of IkappaB-alpha in both neonatal and adult monocytes. We conclude that TLR8 agonists are uniquely efficacious in activating costimulatory responses in neonatal APCs and suggest that these agents are promising candidate adjuvants for enhancing immune responses in human newborns.


Assuntos
Adjuvantes Imunológicos/farmacologia , Células Apresentadoras de Antígenos/imunologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Monócitos/imunologia , Receptor 8 Toll-Like/agonistas , Adulto , Infecções Bacterianas/imunologia , Infecções Bacterianas/metabolismo , Humanos , Proteínas I-kappa B/imunologia , Proteínas I-kappa B/metabolismo , Recém-Nascido , Sistema de Sinalização das MAP Quinases/imunologia , Monócitos/metabolismo , Inibidor de NF-kappaB alfa , Fosforilação/efeitos dos fármacos , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Processamento de Proteína Pós-Traducional/imunologia , Receptor 7 Toll-Like/agonistas , Receptor 7 Toll-Like/metabolismo , Receptor 8 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/imunologia , Proteínas Quinases p38 Ativadas por Mitógeno/imunologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
13.
J Immunol ; 176(6): 3830-9, 2006 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-16517754

RESUMO

The innate ability of B lymphoma cells to escape control by tumor-reactive T cells must be overcome to develop effective immunotherapies for these diseases. Because signals from both the innate and adaptive immune systems direct the acquisition of strong immunogenicity by professional APCs, the effects of IL-2 and the TLR-7 agonist, S28690, on the immunogenic properties of chronic lymphocytic leukemia (CLL) B cells were studied. IL-2 with S28690 caused CLL cells to proliferate and increased their expression of B7-family members, production of TNF-alpha and IL-10, and levels of tyrosine-phosphorylated STAT-1 and STAT-3 proteins. S28690 increased CD25 expression on CLL cells and sensitized them to IL-2 signaling. However, IL-2 did not change TLR-7 expression or signaling in CLL cells. The ability to stimulate T cell proliferation required additional activation of protein kinase C, which inhibited tumor cell proliferation, "switched off" IL-10 production, and caused essentially all CLL cells (regardless of clinical stage) to acquire a CD83(high)CD80(high)CD86(high)CD54(high) surface phenotype marked by the activation of STAT-1 without STAT-3. These findings suggest that TLR-7 "licenses" human B cells to respond to cytokines of the adaptive immune system (such as IL-2) and provide a strategy to increase the immunogenicity of lymphoma cells for therapeutic purposes.


Assuntos
Interleucina-2/imunologia , Linfoma de Células B/imunologia , Linfoma de Células B/metabolismo , Transdução de Sinais , Receptor 7 Toll-Like/imunologia , Receptor 7 Toll-Like/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Células Cultivadas , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Imidazóis/farmacologia , Leucemia Linfocítica Crônica de Células B/imunologia , Leucemia Linfocítica Crônica de Células B/metabolismo , Linfoma de Células B/patologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Proteína Quinase C/metabolismo , Quinolinas/farmacologia , Receptores de Interleucina-2/genética , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT3/metabolismo
14.
J Invest Dermatol ; 126(4): 821-31, 2006 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16439962

RESUMO

Imiquimod (1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine) is a TLR7 agonist that induces cytokine production in TLR7 bearing antigen-presenting cells (APCs), including IL-12, a cytokine that has been demonstrated to be a critical effector molecule for contact hypersensitivity (CHS). To test our hypothesis that topical applications of imiquimod may protect the skin immune system against the deleterious effects of UV light exposures, we treated animals with this agent, or its vehicle or nothing before UV exposures. Although topical imiquimod exposures before UV light did not prevent the depletion of epidermal Langerhans cells, it did prevent the loss of CHS. IL-12 was important in the protective role of imiquimod in preventing UV-induced loss of CHS, as systemic treatment of mice with an anti-IL-12 p70 monoclonal antibody blocked the protective effects of imiquimod. Additionally, only imiquimod-treated mice were resistant to hapten-specific tolerance induction after UV irradiation at the site of the initial sensitization with the hapten 2,4 dinitro-1-fluorobenzene. To model for the effects of TLR7 activation on the UV effect on antigen-APCs, XS52 cell line was used to study this interaction in an in vitro model system. This cell line expressed mRNA for TLR7, downregulated IkappaB, phosphorylated c-Jun N-terminal kinase, and secreted cytokines after exposure to imiquimod or lipopolysaccharide. Activation of the TLR7 signaling pathway on XS52 before UV-light exposures enhanced IL-12p70 secretion by this cell line. Similarly, activation of TLR7 on XS52 before UV-light exposure also prevented the UV-induced loss of IFN-gamma triggering in T cells during an allogeneic mixed lymphocyte reaction. Imiquimod-treated, UV-irradiated XS52 triggered a more vigorous IFN-gamma production than did either imiquimod-treated XS52 or UV-irradiated XS52, again suggesting a synergy between the two treatments. Lastly, enriched lymph node CD11c+ APCs from mice treated with UV irradiation, imiquimod alone or the combination of UV irradiation and imiquimod indicated the same in vivo synergy between imiquimod irradiation and UV irradiation in enhancing IL-12p70 production. These data suggest that topical imiquimod applications may play a role in preventing UV-induced impairment of the skin immune system, which is thought to be one of the critical events that allow the development of UV-induced skin cancers.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Aminoquinolinas/administração & dosagem , Dermatite de Contato/prevenção & controle , Tolerância Imunológica/efeitos dos fármacos , Células de Langerhans/efeitos dos fármacos , Pele/efeitos dos fármacos , Raios Ultravioleta/efeitos adversos , Animais , Anticorpos Monoclonais/farmacologia , Feminino , Proteínas I-kappa B/metabolismo , Imiquimode , Interferon gama/metabolismo , Interleucina-12/antagonistas & inibidores , Interleucina-12/metabolismo , Células de Langerhans/efeitos da radiação , Glicoproteínas de Membrana/agonistas , Camundongos , Camundongos Endogâmicos C57BL , Pele/efeitos da radiação , Receptor 7 Toll-Like/agonistas
15.
Immunity ; 23(5): 465-78, 2005 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16286015

RESUMO

Five TLRs are thought to play an important role in antiviral immunity, sensing viral products and inducing IFN-alpha/beta and -lambda. Surprisingly, patients with a defect of IRAK-4, a critical kinase downstream from TLRs, are resistant to common viruses. We show here that IFN-alpha/beta and -lambda induction via TLR-7, TLR-8, and TLR-9 was abolished in IRAK-4-deficient blood cells. In contrast, IFN-alpha/beta and -lambda were induced normally by TLR-3 and TLR-4 agonists. Moreover, IFN-beta and -lambda were normally induced by TLR-3 agonists and viruses in IRAK-4-deficient fibroblasts. We further show that IFN-alpha/beta and -lambda production in response to 9 of 11 viruses tested was normal or weakly affected in IRAK-4-deficient blood cells. Thus, IRAK-4-deficient patients may control viral infections by TLR-3- and TLR-4-dependent and/or TLR-independent production of IFNs. The TLR-7-, TLR-8-, and TLR-9-dependent induction of IFN-alpha/beta and -lambda is strictly IRAK-4 dependent and paradoxically redundant for protective immunity to most viruses in humans.


Assuntos
Interferons/imunologia , Interferons/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/imunologia , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Receptores Toll-Like/imunologia , Receptores Toll-Like/metabolismo , Vírus/imunologia , Fibroblastos , Regulação da Expressão Gênica , Humanos , Quinases Associadas a Receptores de Interleucina-1 , Fosfotransferases (Aceptor do Grupo Álcool)/deficiência , Poli I-C/imunologia , Transdução de Sinais , Receptor 7 Toll-Like/agonistas , Receptor 7 Toll-Like/imunologia , Receptor 7 Toll-Like/metabolismo , Receptor 8 Toll-Like/agonistas , Receptor 8 Toll-Like/imunologia , Receptor 8 Toll-Like/metabolismo , Receptor Toll-Like 9/agonistas , Receptor Toll-Like 9/imunologia , Receptor Toll-Like 9/metabolismo , Receptores Toll-Like/agonistas , Viroses/imunologia , Viroses/metabolismo , Viroses/virologia
16.
Leuk Lymphoma ; 46(6): 935-9, 2005 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16019542

RESUMO

The identification of clinically relevant, active immunomodulatory agents is important for developing immunotherapeutic approaches to chronic lymphocytic leukemia (CLL) and other B-cell lymphomas that are not curable with conventional chemotherapy. In this investigation, the imidazoquinoline Toll-like receptor (TLR)-7/8 agonist, imiquimod, was found to mediate the clearance of a lymphomatous skin lesion in a CLL patient. Imidazoquinolines also activated TLR-7/8 signaling pathways, resulting in increased expression of costimulatory molecules on circulating tumor cells. These observations extend the therapeutic spectrum of imiquimod to cutaneous B-cell lymphomas and suggest the use of TLR-7/8 agonists in CLL immunotherapy.


Assuntos
Aminoquinolinas/uso terapêutico , Antineoplásicos/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Linfoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Receptor 7 Toll-Like/agonistas , Receptor 8 Toll-Like/agonistas , Idoso , Progressão da Doença , Humanos , Imiquimode , Imunoterapia/métodos , Leucemia Linfocítica Crônica de Células B/patologia , Linfoma/patologia , Masculino , Transdução de Sinais , Neoplasias Cutâneas/patologia , Resultado do Tratamento
17.
J Med Chem ; 48(10): 3481-91, 2005 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-15887957

RESUMO

1H-Imidazo-[4,5-c]quinolines were prepared while investigating novel nucleoside analogues as potential antiviral agents. While these compounds showed no direct antiviral activity when tested in a number of cell culture systems, some demonstrated potent inhibition of virus lesion development in an intravaginal guinea pig herpes simplex virus-2 assay. We have determined that the in vivo antiviral activity can be attributed to the ability of these molecules to induce the production of cytokines, especially interferon (IFN), in this model. Subsequently, we found that the compounds also induce in vitro production of IFN in human peripheral blood mononuclear cells (hPBMCs). The in vitro results reported herein and the in vivo results reported previously led to the discovery of imiquimod, 26, which was developed as a topical agent and has been approved for the treatment of genital warts, actinic keratosis, and superficial basal cell carcinoma.


Assuntos
Aminoquinolinas/síntese química , Antivirais/síntese química , Imidazóis/síntese química , Indutores de Interferon/síntese química , Interferons/biossíntese , Quinolinas/síntese química , Aminoquinolinas/química , Aminoquinolinas/farmacologia , Animais , Antivirais/química , Antivirais/farmacologia , Linhagem Celular Tumoral , Células Cultivadas , Efeito Citopatogênico Viral/efeitos dos fármacos , Cobaias , Herpesvirus Humano 2/efeitos dos fármacos , Humanos , Imidazóis/química , Imidazóis/farmacologia , Imiquimode , Indutores de Interferon/química , Indutores de Interferon/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Quinolinas/química , Quinolinas/farmacologia , Relação Estrutura-Atividade
19.
Int J Oral Maxillofac Implants ; 19(4): 491-7, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-15346745

RESUMO

PURPOSE: The aim of this randomized, controlled, blinded clinical study was to compare ridge dimensions and histologic characteristics of ridges preserved with 2 different graft materials. MATERIALS AND METHODS: Twenty-four subjects, each requiring a nonmolar extraction and delayed implant placement, were randomly selected to receive ridge preservation treatment with either an allograft in an experimental putty carrier plus a calcium sulfate barrier (PUT) or a bovine-derived xenograft (BDX) plus a collagen membrane. Horizontal and vertical ridge dimensions were determined using a digital caliper and a template. At 4 months postextraction, a trephine core was obtained for histologic analysis. RESULTS: The average ridge width decreased by 0.50 mm for both groups (P < .05). The midbuccal vertical change for the PUT group was a loss of 0.3+/-0.7 mm versus a gain of 0.7+/-1.2 mm for the BDX group, a difference of 1.0 mm (P > .05). Histologic analysis revealed vital bone in the PUT group of about 61%+/-9% versus 26%+/-20% for the BDX group (P < .05). DISCUSSION: Greater vital bone fill in the PUT group may be attributable to earlier and greater vascular invasion of the carrier material. The putty material was characterized by ease of handling, simple placement, and enhanced graft particle containment. CONCLUSIONS: Allograft mixed with an experimental putty carrier produced significantly more vital bone fill than did the use of a xenograft with no carrier material. Ridge width and height dimensions were similarly preserved with both graft materials.


Assuntos
Perda do Osso Alveolar/prevenção & controle , Aumento do Rebordo Alveolar/métodos , Regeneração Óssea , Transplante Ósseo/métodos , Animais , Matriz Óssea/transplante , Substitutos Ósseos , Sulfato de Cálcio , Carboximetilcelulose Sódica , Bovinos , Colágeno , Método Duplo-Cego , Portadores de Fármacos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Minerais , Alvéolo Dental
20.
J Periodontol ; 74(7): 990-9, 2003 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-12931761

RESUMO

BACKGROUND: Tooth extraction typically leads to loss of ridge width and height. The primary aim of this 6-month randomized, controlled, blinded, clinical study was to determine whether ridge preservation would prevent post-extraction resorptive changes as assessed by clinical and histologic parameters. METHODS: Twenty-four patients, 10 males and 14 females, aged 28 to 76 (mean 51.5 +/- 13.6), requiring a non-molar extraction and delayed implant placement were randomly selected to receive either extraction alone (EXT) or ridge preservation (RP) using tetracycline hydrated freeze-dried bone allograft (FDBA) and a collagen membrane. A replaced flap, which did not completely cover the sockets, was used. Following extraction, horizontal and vertical ridge dimensions were determined using a modified digital caliper and an acrylic stent, respectively. Prior to implant placement, a 2.7 x 6.0 mm trephine core was obtained and preserved in formalin for histologic analysis. RESULTS: The width of the RP group decreased from 9.2 +/- 1.2 mm to 8.0 +/- 1.4 mm (P<0.05), while the width of the EXT group decreased from 9.1 +/- 1.0 mm to 6.4 +/- 2.2 mm (P<0.05), a difference of 1.6 mm. Both the EXT and RP groups lost ridge width, although an improved result was obtained in the RP group. Most of the resorption occurred from the buccal; maxillary sites lost more width than mandibular sites. The vertical change for the RP group was a gain of 1.3 +/- 2.0 mm versus a loss of 0.9 +/- 1.6 mm for the EXT group (P<0.05), a height difference of 2.2 mm. Histologic analysis revealed more bone in the RP group: about 65 +/- 10% versus 54 +/- 12% in the EXT group. The RP group included both vital bone (28%) and non-vital (37%) FDBA fragments. CONCLUSIONS: Ridge preservation using FDBA and a collagen membrane improved ridge height and width dimensions when compared to extraction alone. These dimensions may be more suitable for implant placement, especially in areas where loss of ridge height would compromise the esthetic result. The quantity of bone observed on histologic analysis was slightly greater in preservation sites, although these sites included both vital and non-vital bone. The most predictable maintenance of ridge width, height, and position was achieved when a ridge preservation procedure was employed.


Assuntos
Alveoloplastia/métodos , Transplante Ósseo/métodos , Colágeno , Implantes Dentários , Membranas Artificiais , Extração Dentária , Adulto , Idoso , Processo Alveolar/patologia , Análise de Variância , Reabsorção Óssea/prevenção & controle , Feminino , Seguimentos , Liofilização , Humanos , Masculino , Mandíbula/patologia , Mandíbula/cirurgia , Maxila/patologia , Maxila/cirurgia , Pessoa de Meia-Idade , Método Simples-Cego , Preservação de Tecido , Alvéolo Dental/patologia , Alvéolo Dental/cirurgia
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