RESUMO
Background: The prevalence and mortality of sepsis in Internal Medicine Units (IMUs) is poorly understood as most of the data derive from studies conducted in Intensive Care Units. Aim of SEpsis Management in INternal medicine Apulia (SEMINA) study was to determine the prevalence of sepsis and the characteristics and outcomes of patients with Sepsis-3 criteria admitted in Apulia's Internal Medicine Units for over six months. Methods: The SEpsis Management in INternal medicine of Apulia study was a prospective, multicentre, observational study. Adult admissions to the 13 Apulia Region's Internal Medicine Units between November 15, 2018 and May 15, 2019 were screened for sepsis according to the Sepsis-3 criteria. Medical data were collected in electronic case report form. Results: Out of 7,885 adult patients of the Internal Medicine Units, 359 (4.55%) fulfilled the inclusion criteria, and 65 of them (18.1%) met the septic shock criteria. The patients enrolled were elderly, suffering from chronic poly-pathologies and from cognitive and functional impairment. The respiratory system was the most common site of infection and the most common pathogens isolated from blood cultures were Staphylococcus spp., E. coli, Klebsiella spp., Enterococcus spp. and Acinetobacter spp. The in-hospital fatality rate was 31.2% and was significantly higher for septic shock. Sequential Organ Failure Assessment score, dementia and infections from Acinetobacter spp. were independent risk factors for mortality. Conclusions: A high prevalence of sepsis and a high fatality rate were detected in Apulia Region's Internal Medicine Units. The high fatality rate observed in our study could be related to the underlying diseases and to the vulnerability of elderly patients admitted to our Internal Medicine Units.
Assuntos
Sepse , Choque Séptico , Adulto , Idoso , Humanos , Mortalidade Hospitalar , Unidades de Terapia Intensiva/estatística & dados numéricos , Estudos Prospectivos , Sepse/epidemiologia , Sepse/microbiologia , Sepse/terapia , Choque Séptico/epidemiologia , Choque Séptico/microbiologia , Choque Séptico/terapia , PrevalênciaRESUMO
The current study examined whether alexithymia is involved in colon cancer as has been found in breast and uterine cancer research. The TAS-20 was administered before examination to patients who underwent colon cancer screening. Histological data were obtained from the biopsies. Gender, age, education, smoking and drinking habits, and personal and family histories of neoplastic colonic disease were controlled for in the analysis. Both adenoma and adenocarcinoma patients had higher TAS-20 scores than negative cases, and both high and intermediate levels of alexithymia were implicated. Difficulty identifying feelings and externally oriented thinking were the most prominent facets related to the disease process.
Assuntos
Sintomas Afetivos/epidemiologia , Sintomas Afetivos/psicologia , Neoplasias do Colo/epidemiologia , Neoplasias do Colo/psicologia , Colonoscopia , Programas de Rastreamento/métodos , Comorbidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica/estatística & dados numéricos , Fatores de Risco , Cidade de Roma/epidemiologia , Inquéritos e QuestionáriosRESUMO
M proteins that define the serotypes of group A streptococci are powerful blastogens for human T lymphocytes. The mechanism by which they activate T cells was investigated and compared with the conventional T cell mitogen phytohemagglutinin, and the known superantigen staphylococcal enterotoxin B. Although major histocompatibility complex (MHC) class II molecules are required for presentation, there is no MHC restriction, since allogeneic class II molecules presented the bacterial protein to human T cells. Type 5 M protein appears to bind class II molecules on the antigen-presenting cells and stimulate T cells bearing V beta 8 sequences. Our results indicate that this streptococcal M protein is a superantigen and suggest a possible mechanism of its role in the pathogenesis of the postinfectious autoimmune sequelae.
Assuntos
Antígenos de Bactérias , Proteínas da Membrana Bacteriana Externa , Proteínas de Bactérias/imunologia , Proteínas de Transporte , Linfócitos T/imunologia , Anticorpos Monoclonais , Células Apresentadoras de Antígenos/imunologia , Enterotoxinas/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Humanos , Ativação Linfocitária/imunologia , Fito-Hemaglutininas/imunologiaRESUMO
M proteins, the major virulence factor of group A streptococci, have been implicated in the pathogenesis of acute rheumatic fever (ARF) and other streptococcal related autoimmune diseases. A 22-kD fragment of M type 5 protein is a potent stimulant of human T cells and has recently been shown by our laboratory to belong to the newly designated family of superantigens. Using flow cytometry and the polymerase chain reaction, we demonstrate that this molecule reacts with subsets of human T cells expressing specific T cell receptor (TCR) V beta elements, namely V beta 2, 4, and 8. We employed similar techniques to analyze the TCR V alpha usage of pep M5-stimulated T cells. These studies revealed that the preferential usage of particular V alpha elements is not specific for the superantigen; rather, it may reflect the repertoire of the individual being tested. The expansion of a large number of T cells bearing specific TCR V beta sequences by M protein may account for its role in mediating the pathogenesis of post-streptococcal diseases. Furthermore, the preferential usage of TCR V alpha elements in certain individuals may be an important factor that predisposes them to development of self-reactivity.
Assuntos
Proteínas da Membrana Bacteriana Externa , Proteínas de Bactérias/farmacologia , Proteínas de Transporte , Receptores de Antígenos de Linfócitos T/genética , Linfócitos T/imunologia , Antígenos de Bactérias , Sequência de Bases , Células Cultivadas , Humanos , Substâncias Macromoleculares , Dados de Sequência Molecular , Sondas de Oligonucleotídeos , Reação em Cadeia da Polimerase , RNA/genética , RNA/isolamento & purificação , Linfócitos T/efeitos dos fármacosRESUMO
OBJECTIVE: The aim of the present study was to assess the association among anxiety, depression, stress, social support and emotional abilities with adherence and healthcare spending in type 2 diabetic patients. PATIENTS AND METHODS: Sixty-four patients were enrolled and completed: Interpersonal Processes of Care (IPC), 20-item Toronto Alexithymia Scale (TAS-20), Rapid Stress Assessment Scale (RSAS), Morisky Medication Adherence Scale (MMAS-4), International Physical Activity Questionnaire (IPAQ)-Short Form and a socio-anamnestic questionnaire regarding also the healthcare spending. RESULTS: Mathematical linear regressions models were performed showing the predictive effects of: anxiety and social support scores (RSAS) on adherence levels (respectively p =. 019; p =. 016); adherence levels on anxiolytic use (p =.04); aggressiveness scores (RSAS) on the number of general check-ups (p =.031); TAS-20 and physician-patient communication (IPC) on the number of hospitalization days (respectively p=.001; p=.008); physician patient decision making (IPC) scores on physical activity (IPAQ) levels (p=.025); physical activity (IPAQ) on the number of medical examinations (p=.039). CONCLUSIONS: An association among psychosocial impairment, adherence and healthcare spending was found. Future studies should investigate the effect of a brief psychological intervention in increasing adherence levels and reducing the healthcare spending in this clinical population.
Assuntos
Diabetes Mellitus Tipo 2/psicologia , Gastos em Saúde/estatística & dados numéricos , Adesão à Medicação/estatística & dados numéricos , Apoio Social , Idoso , Idoso de 80 Anos ou mais , Ansiedade/diagnóstico , Ansiedade/economia , Ansiedade/epidemiologia , Ansiedade/psicologia , Depressão/diagnóstico , Depressão/economia , Depressão/epidemiologia , Depressão/psicologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/economia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Psicometria/estatística & dados numéricos , Autorrelato/estatística & dados numéricos , Estresse Psicológico/diagnóstico , Estresse Psicológico/economia , Estresse Psicológico/epidemiologia , Estresse Psicológico/psicologiaRESUMO
The imidazoquinolineamine derivative 1-(2-methyl propyl)-1H-imidazole [4,5-c]quinoline-4-amine (imiquimod) has been shown to induce alpha interferon (IFN-alpha) synthesis both in vivo and in peripheral blood mononuclear cells in vitro. In this study, we show that, in these cells, imiquimod induces expression of several IFNA genes (IFNA1, IFNA2, IFNA5, IFNA6, and IFNA8) as well as the IFNB gene. Imiquimod also induced the expression of interleukin (IL)-6, IL-8, and tumor necrosis factor alpha genes. Expression of all these genes was transient, independent of cellular protein synthesis, and inhibited in the presence of tyrosine kinase and protein kinase C inhibitors. Infection with Sendai virus led to expression of a similar set of cytokine genes and several of the IFNA genes. Imiquimod stimulates binding of several induction-specific nuclear complexes: (i) the NF-kappa B-specific complexes binding to the kappa B enhancer present in the promoters of all cytokine genes, but not in IFNA genes, and (ii) the complex(es) binding to the A4F1 site, 5'-GTAAAGAAAGT-3', conserved in the inducible element of IFNA genes. These results indicate that imiquimod, similar to viral infection, stimulates expression of a large number of cytokine genes, including IFN-alpha/beta, and that the signal transduction pathway induced by both of these stimuli requires tyrosine kinase and protein kinase activity.
Assuntos
Aminoquinolinas/farmacologia , Citocinas/biossíntese , Indutores de Interferon/farmacologia , Leucócitos Mononucleares/fisiologia , Transdução de Sinais/fisiologia , Animais , Sequência de Bases , Células Cultivadas , Citocinas/genética , Expressão Gênica , Humanos , Imiquimode , Interferons/biossíntese , Interferons/classificação , Interferons/genética , Interleucinas/biossíntese , Interleucinas/genética , Leucócitos Mononucleares/classificação , Camundongos , Dados de Sequência Molecular , NF-kappa B/metabolismo , Vírus da Parainfluenza 1 Humana/fisiologia , Ligação Proteica , Inibidores de Proteínas Quinases , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/genéticaRESUMO
Weak immunogenicity of chronic lymphocytic leukemia (CLL) cells may contribute to disease progression and inhibit effective immunotherapy. Accordingly, agents that enhance the immunogenicity of CLL cells may be useful in immunotherapeutic approaches to this disease. Since Toll-like receptors (TLRs) are major regulators of innate immunity and initiation of adaptive immunity, we studied the effects of viral pathogen associated molecular pattern agonists (that are recognized by TLRs) on the costimulatory phenotype and function of CLL cells. CLL cells (especially those with high endogenous expression of CD38) responded to TLR7-activating imidazoquinolines and guanosine analogs by increasing costimulatory molecule expression, producing inflammatory cytokines, and becoming more sensitive to killing by cytotoxic effectors. Additional activation of protein kinase C pathways increased the ability to stimulate T-cell proliferation, blocked phosphorylation of the transcription factor, signal transducer and activator of transcription (STAT)3, and resulted in the acquisition of a dendritic cell surface phenotype by TLR7-activated CLL cells. Normal B cells also responded to TLR7 activation by increasing costimulatory molecule expression and cytokine production. These findings suggest a potential role for TLR7 agonists in CLL immunotherapy.
Assuntos
Imidazóis/farmacologia , Fatores Imunológicos/farmacologia , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/metabolismo , Ésteres de Forbol/farmacologia , Quinolinas/farmacologia , Receptor 7 Toll-Like/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos B/efeitos dos fármacos , Linfócitos B/metabolismo , Quimiocinas/biossíntese , Citocinas/biossíntese , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/imunologia , Masculino , Pessoa de Meia-Idade , Fator de Transcrição STAT3/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo , Sensibilidade e Especificidade , Receptor 7 Toll-Like/efeitos dos fármacos , Células Tumorais CultivadasRESUMO
The requirement for co-stimulatory molecules in T-cell stimulation by mitogens and superantigens in the absence of antigen-presenting cells (APC) was investigated. Phytohemagglutinin (PHA) induced interleukin (IL)-2 receptor (IL-2R) expression on purified T-cells, but proliferation occurred only when exogenous IL-2 was added. In contrast, the proliferative response to a pepsin-extracted type 5 M-protein from Streptococcus pyogenes (pep M5), a recently identified superantigen, required signals provided by phorbol 12-myristate 13-acetate (PMA), IL-1 and IL-6. pep M5 alone did not induce IL-2R expression; however, when combined with PMA, IL-1 and IL-6, IL-2R was expressed. Differences were also observed in the response of the leukemic T-cell line, Jurkat, to PHA and pep M5. Soluble PHA, but not pep M5, induced IL-2 production by these cells in the presence of PMA. Cross-linking by its specific antibody or adsorption of pep M5 to microtiter plates was required to activate Jurkat cells. Both PHA and pep M5 induced Ca2+ mobilization in Jurkat cells; however, only PHA induced a rise in intracellular Ca2+ in purified T-cells, whereas pep M5 was unable to induce this activity unless IL-1, IL-6 and PMA were added. Our data provide biochemical evidence that mitogenic and superantigenic stimulation of T-cells is different.
Assuntos
Antígenos de Bactérias/imunologia , Proteínas da Membrana Bacteriana Externa , Proteínas de Transporte , Citocinas/fisiologia , Ativação Linfocitária/imunologia , Mitógenos/farmacologia , Linfócitos T/imunologia , Células Apresentadoras de Antígenos/fisiologia , Proteínas de Bactérias/imunologia , Cálcio/metabolismo , Humanos , Interleucina-1/farmacologia , Interleucina-2/metabolismo , Interleucina-6/farmacologia , Fragmentos de Peptídeos/imunologia , Fito-Hemaglutininas/farmacologia , Receptores de Interleucina-2/metabolismo , Acetato de Tetradecanoilforbol/farmacologia , Células Tumorais CultivadasRESUMO
Although the C3H/HeJ mouse is hyporesponsive to lipopolysaccharides (LPS), certain forms of the lipid A fraction have been shown to stimulate cells from this mouse strain. To determine the role of the oligosaccharide chain length on the lipid A-induced proliferation of C3H/HeJ splenocytes, a panel of glycolipids from R-chemotypes (Re, Rc, and Rd) and a nontoxic monophosphoryl lipid A (MPL) were tested. The MPL cells isolated from the MPL of Salmonella minnesota, Salmonella typhimurium, and the Reglycolipids isolated from Escherichia coli were found to be effective at stimulating the LPS-hyporesponsive spleen cells. A Re-glycolipid isolated from a different strain of E. coli cells was inactive, as were the S. minnesota Rc and Rd chemotypes. Proliferation induced by MPL and the active Re preparations was dose dependent and was inhibited by polymyxin B. Thus, if contamination of the Re-LPS or MPL with lipid A-associated protein occurred, it was below functional levels. The data suggest that the C3H/HeJ spleen cells are capable of responding to certain glycolipids, but they may lack the ability to convert native LPS into a stimulatory signal. In addition, a monosaccharide precursor of lipid A (lipid X), and a monoacyl glucosamine phospholipid derivative of lipid X (MaGP), were capable of inhibiting the proliferation induced by the MPL and Re-glycolipids. These data are compatible with the existence of a spleen cell receptor for lipid A.
Assuntos
Glicolipídeos/farmacologia , Lipídeo A/análogos & derivados , Ativação Linfocitária/efeitos dos fármacos , Baço/citologia , Animais , Divisão Celular/efeitos dos fármacos , Escherichia coli/análise , Glicolipídeos/isolamento & purificação , Lipídeo A/isolamento & purificação , Lipídeo A/farmacologia , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C3H , Polimixina B/farmacologia , Salmonella/análiseRESUMO
We have developed an animal model for congenital syphilis. Treponema pallidum is injected intravenously into pregnant rabbits and fetuses are infected in utero. As a prelude to characterizing the immunologic consequences of fetal infection, it was necessary to expand on the baseline information about newborn rabbit immune capabilities. Studies were undertaken to determine splenic macrophage and T lymphocyte functions with emphasis on newer immunologic parameters. Newborns aged 2 weeks were compared to adults. Macrophage capabilities in newborn rabbits differed from those of their adult counterparts. These cells produced similar basal levels of interleukin 1 (IL-1) but failed to respond to the IL-1 stimulants of lipopolysaccharide (LPS) or T. pallidum. Macrophages also exhibited diminished levels of la expression and increased levels of prostaglandin E2 (PGE2) secretion. T lymphocyte functions were altered in newborn spleen preparations. Following concanavalin A (Con A) stimulation, interferon gamma production was half that of adults; in direct contrast, IL-2 production was twice that of adults. Con A-induced lymphocyte proliferation was markedly decreased in newborn preparations. This diminished response resulted from down-regulation rather than immaturity. When newborn splenic cells were stimulated with Con A in the presence of indomethacin, anti-transforming growth factor (anti-TGF), or exogenous IL-1/IL-2, better proliferation resulted. PGE2, which is well established as a down-regulator of newborn immune functions in human and mouse systems, also appears to play a role in suppressing newborn rabbit functions. TGF is a potent suppressor of a number of adult immunologic reactions. This is the first documentation of the potential role of this factor in down-regulating newborn immune capabilities. These findings provide a framework for future investigations of our congenital syphilis model.
Assuntos
Animais Recém-Nascidos/imunologia , Linfócitos/imunologia , Macrófagos/imunologia , Animais , Dinoprostona/farmacologia , Antígenos de Histocompatibilidade Classe II/metabolismo , Imunidade Celular , Indometacina/farmacologia , Interferon gama/farmacologia , Interleucina-1/fisiologia , Interleucina-2/fisiologia , Ativação Linfocitária/efeitos dos fármacos , Coelhos , Baço/citologia , Sífilis Congênita/imunologia , Fatores de Crescimento Transformadores/farmacologiaRESUMO
Imiquimod has been identified as a potent antiviral and antitumor agent in animal models. The biological activity associated with imiquimod has been attributed to its induction of interferon (IFN)-alpha. The present studies evaluated imiquimod administered orally for its ability to stimulate production of IFN and other cytokines in mice. The cytokine profile induced by imiquimod was compared with other known immunomodulators. Imiquimod was found to stimulate increased serum IFN in mice. Daily dosing of imiquimod for five consecutive days led to diminished production of IFN in mice as measured after the final dose. Elevated levels of serum tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 but not IL-1 alpha were found in serum from mice treated with imiquimod. Imiquimod produced significantly higher levels of IFN but lower levels of TNF and IL-6 and IL-1 alpha than lipopolysaccharide. Polyinosinic acid:polycytidylic acid induced significantly higher amounts of IFN but lower levels of TNF and IL-6 than imiquimod. Imiquimod stimulated significantly higher levels of IFN when compared with 2-amino-5-bromo-6-phenyl-4(3H)-pyrimidinone (ABPP) and similar levels of IFN when compared with tilorone. Neither ABPP nor tilorone induced TNF or IL-6. Finally, imiquimod stimulated TNF, IFN, and IL-6 production in cultures of mouse spleen and bone marrow cells. These studies demonstrate that imiquimod induces not only IFN but other cytokines as well, all of which may contribute to its biological activity.
Assuntos
Aminoquinolinas/farmacologia , Medula Óssea/metabolismo , Citocinas/biossíntese , Indutores de Interferon/farmacologia , Interferons/biossíntese , Lipopolissacarídeos/farmacologia , Linfócitos/metabolismo , Animais , Medula Óssea/efeitos dos fármacos , Células da Medula Óssea , Células Cultivadas , Citosina/análogos & derivados , Citosina/farmacologia , Relação Dose-Resposta a Droga , Ensaio de Imunoadsorção Enzimática , Imiquimode , Interferons/sangue , Interleucina-1/biossíntese , Interleucina-1/sangue , Interleucina-6/biossíntese , Cinética , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos , Poli I-C/farmacologia , Salmonella typhimurium , Baço/citologia , Tilorona/farmacologia , Fatores de Tempo , Fator de Necrose Tumoral alfa/biossínteseRESUMO
Imiquimod (R-837, S-26308) and the analogue S-27609 were evaluated for cytokine induction in human blood cells. Both compounds induced interferon-alpha (IFN), tumor necrosis factor-alpha (TNF), interleukin (IL)-1 beta, and IL-6 with S-27609 being 5 to 10 times more potent. Imiquimod and S-27609 also induced IL-1 alpha, IL-1 receptor antagonist, IL-10, granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte CSF (G-CSF), and macrophage inflammatory protein-1 alpha. The profile of cytokines induced by imiquimod and S-27609 was different from those seen with lipopolysaccharide and polyinosinic-polycytidylic acid. Kinetic studies with both imiquimod and S-27609 revealed induction of cytokines as early as 1-4 h after stimulation. Although most of the cytokines produced by S-27609 were secreted, significant concentrations of IL-1 alpha and IL-1 beta remained intracellular. Monocytes were largely responsible for the cytokines produced. Finally, S-27609-induced mRNA expression for TNF, IFN, and IL-8, and this induction did not require protein synthesis. Taken together, these studies extend previous findings by showing induction of additional cytokines and providing insight into the mechanism of cytokine induction by these molecules.
Assuntos
Adjuvantes Imunológicos , Aminoquinolinas/farmacologia , Citocinas/biossíntese , Indutores de Interferon , Células Cultivadas , Cicloeximida/farmacologia , Citocinas/genética , Dactinomicina/farmacologia , Expressão Gênica/efeitos dos fármacos , Humanos , Imiquimode , Técnicas In Vitro , RNA Mensageiro/genéticaRESUMO
This investigation compared the immunomodulating activities of two forms monophosphoryl lipid A, which are analogues of bacterial lipopolysaccharides with little or no toxicity. Tested were a synthetic compound designated 504 and a purified compound, isolated from bacterial cell walls designated MPL. Both of these clinical adjuvant candidates were effective in mice in exerting strong immunomodulating activity in the following areas: (a) enhancing antibody production in young and aging mice; (b) suppressing antibody formation under different experimental conditions; (c) activating macrophages to secrete interleukin 1, hydrogen peroxide, and superoxide anion; and (d) stimulating proliferation of spleen cells from C3H/HeN mice. Both exhibited considerably reduced toxicity in LD50 assays when compared to native lipopolysaccharides (LPS). The LD50 for MPL was 225 times and that of compound 504, 40 times that of native LPS in the exquisitely sensitive, galactosamine-loaded C57BL/6 murine strain.
Assuntos
Adjuvantes Imunológicos/farmacologia , Lipídeo A/análogos & derivados , Adjuvantes Imunológicos/isolamento & purificação , Adjuvantes Imunológicos/toxicidade , Envelhecimento/imunologia , Animais , Formação de Anticorpos/efeitos dos fármacos , Técnicas In Vitro , Dose Letal Mediana , Lipídeo A/isolamento & purificação , Lipídeo A/farmacologia , Lipídeo A/toxicidade , Ativação Linfocitária/efeitos dos fármacos , Ativação de Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos EndogâmicosRESUMO
Langerhans cells are bone marrow derived dendritic cells that represent the major antigen-presenting cells in the skin. Langerhans cells take up and process antigen within the epidermis and present processed antigen to T lymphocyte in the regional lymph nodes and thus form an integral part of the cutaneous immune response. The cutaneous immune response can be modified by a number of pharmacologic agents, including corticosteroids, cyclosporine, and retinoids as well as physical agents, such as ultraviolet light. For the most part these agents act by suppressing immune function. A topical immune response modifier, imiquimod has been shown to enhance the cutaneous immune response. Imiquimod has anti-viral and anti-tumor effects in animal models and has been approved for the topical treatment of external genital and perianal warts in humans. The biologic activity of imiquimod in part is due to its effect as a cytokine inducer. Preliminary data suggested that imiquimod could have an effect on Langerhans cells. In order to clarify this effect on Langerhans cells, we examined Langerhans cell morphology and migration in imiquimod-treated skin. The density of Ia + cells decreased 2 d after treatment, falling to approximately 43% by day 10. The Ia positive in cells remaining in the skin appeared larger and more dendritic suggesting an activated state. ATPase staining of epidermal sheet confirmed the decreased number of Langerhans cells. To clarify status of Langerhans cells, the activation of B7 was examined. Activation of B7-1 or B7-2 was not detected. Imiquimod, however, did enhance Langerhans cell migration from skin to draining lymph nodes. This enhanced Langerhans cell migration was also associated with an enhanced allergic contact hypersensitivity. These results suggest that the mechanism of modulation of immune response by imiquimod is in part due to effects on Langerhans cells.
Assuntos
Adjuvantes Imunológicos/farmacologia , Aminoquinolinas/farmacologia , Células de Langerhans/efeitos dos fármacos , Adenosina Trifosfatases/metabolismo , Administração Tópica , Animais , Formação de Anticorpos/efeitos dos fármacos , Contagem de Células/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Citocinas/genética , Dermatite de Contato/fisiopatologia , Células Epidérmicas , Antígenos de Histocompatibilidade Classe II/análise , Imiquimode , Células de Langerhans/citologia , Células de Langerhans/enzimologia , Células de Langerhans/imunologia , Células de Langerhans/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , RNA Mensageiro/metabolismo , Regulação para CimaRESUMO
ALDARA (imiquimod cream 5%) recently became available for the treatment of genital and perianal warts; however, the topical mechanism of action of imiquimod is not fully understood. Imiquimod, and its analogs R-842, S-27609, and S-28463, are potent anti-viral and anti-tumor agents in animal models. Much of the biologic activity of these compounds can be attributed to the induction of cytokines, including interferon-alpha, tumor necrosis factor-alpha, interleukins-1, -6, -8, and others. This study was performed to characterize the response of mice and rats to topical application of imiquimod and S-28463 and also to evaluate these agents in cultures of murine and human skin cells. Topical administration of imiquimod or S-28463 to the flanks of hairless mice and rats leads to increases in local concentrations of interferon and tumor necrosis factor in the skin. The concentrations of interferon and tumor necrosis factor were higher at the site of drug application than in skin from the contralateral flank or skin from untreated animals. Interferon-alpha mRNA levels were also elevated in the skin of mice after topical application of either imiquimod or S-28463. In vitro, both imiquimod and S-28463 induced increases in interferon and tumor necrosis factor in cultures of cells isolated from hairless mouse skin. Imiquimod also increased interleukin-8 concentrations in human keratinocyte and fibroblast cultures, whereas S-28463 induced increases in tumor necrosis factor in fibroblast cultures. These results demonstrate that imiquimod and S-28463 stimulate production of cytokines in the skin after topical application, which may play a major role in its activity in genital wart patients.
Assuntos
Adjuvantes Imunológicos/farmacologia , Aminoquinolinas/farmacologia , Citocinas/metabolismo , Pele/metabolismo , Administração Tópica , Animais , Formação de Anticorpos/efeitos dos fármacos , Células Cultivadas , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Imiquimode , Interferon-alfa/genética , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Masculino , Melanócitos/efeitos dos fármacos , Melanócitos/metabolismo , Camundongos , Camundongos Pelados , RNA Mensageiro/metabolismo , Ratos , Ratos Nus , Pele/citologia , Pele/efeitos dos fármacosRESUMO
Imiquimod and its analogs belonging to a class of imidazoquinolinamines, activate immune system via cytokine induction, and have antitumor and antiviral effects in mammals. In this study, we showed that a related analog, designated S-28828, induced interferon (IFN) and macrophage activating cytokine(s) (macrophage activating factor, MAF) in chickens in vivo, ex vivo, and in vitro. IFN and MAF were detectable in the serum of chickens following oral administration. Serum IFN levels were the highest at 2 h after treatment. Although there was no detectable IFN in sera of chickens at 8, 24, and 48 h after treatment, high levels of interferon inducible enzyme, 2'-5' oligoadenylate synthase (2'5'OAS) were present at these time points. In vitro and ex vivo studies showed that spleen cells, bone marrow (BM) cells, and peripheral blood leukocytes (PBL) were capable of producing IFN and MAF, although spleen cells produced the highest levels. Our results suggest that S-28828 administered orally may be a useful immunoenhancing and antiviral agent for chickens.
Assuntos
Aminoquinolinas/uso terapêutico , Citocinas/biossíntese , Sistema Imunitário/efeitos dos fármacos , Indutores de Interferon/uso terapêutico , 2',5'-Oligoadenilato Sintetase/metabolismo , Administração Oral , Animais , Galinhas , Epitopos , Interferon Tipo I/imunologia , Fatores Ativadores de Macrófagos/biossíntese , Proteínas Recombinantes/imunologia , Relação Estrutura-AtividadeRESUMO
A new immunomodulating agent, imiquimod, has been reported to have antiviral and antitumor activities in animal models. S-28463 (4-amino-2-ethoxymethyl-alpha, alpha-dimethyl-1H-imidazo[4, 5-c]quinoline-1-ethanol), an analog of imiquimod, has more potent antiviral activity in animals than imiquimod. It has also been shown to be more potent at inducing cytokines in human blood in vitro. However, its precise role as an immunomodulator in the skin has not been determined. We investigated the effect of S-28463 on human keratinocyte (KC) production of interferon-alpha (IFN-alpha) and other proinflammatory cytokines, including interleukin (IL)-1alpha, IL-8, and tumor necrosis factor-alpha (TNF-alpha). Human KC were incubated with S-28463 at two concentrations (1 microgram/ml and 10 micrograms/ml) for 6 h. Cytokine gene expression was analyzed by reverse-transcriptase PCR. In human KC, S-28463 stimulated significant increases in IFN-alpha mRNA at both concentrations. IL-1alpha mRNA increased 1.4-fold at 10 micrograms/ml. IL-8 mRNA was upregulated 2.5-fold at 10 micrograms/ml. Twenty-four hours after treatment, IL-1 alpha, IL-8, and TNF-alpha protein were increased, but IFN-alpha was below the level of detection. These results suggest that in the skin, S-28463-induced-IL-1 alpha, IL-8, and TNF-alpha production may be involved in the immunomodulating action of S-28463.
Assuntos
Adjuvantes Imunológicos/farmacologia , Aminoquinolinas/farmacologia , Antineoplásicos/farmacologia , Antivirais/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Administração Cutânea , Células Cultivadas , Citocinas/biossíntese , Citocinas/genética , Humanos , Interferon-alfa/genética , Interleucina-1/genética , Interleucina-8/genética , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Reação em Cadeia da Polimerase/métodos , Fator de Necrose Tumoral alfa/genéticaRESUMO
Imiquimod (R-837) and its analog, S-27609, belong to a class of imidazoquinolinamines that have potent antitumor and antiviral effects in animals. Much of their biologic activity is a result of the induction of cytokines, including interferon-alpha (IFN-alpha), tumor necrosis factor alpha (TNF), and others. In this study, the cells responsible for S-27609- and imiquimod-induced cytokine production were characterized. E rosette+ T cells were not the major cell population responsible for IFN-alpha and TNF in response to S-27609 or imiquimod. In contrast, E rosette- cells and unseparated PBMC produced similar concentrations of IFN-alpha and TNF in response to S-27609 and imiquimod. Elimination of monocytes by treatment with the lysosomotropic agent L-leucine methyl ester (LME) or depletion using antibody to CD14 and immunomagnetic beads abrogated IFN-alpha and TNF production induced by S-27609, imiquimod, or LPS but not poly(I)/(C). LME treatment also abolished interleukin (IL)-1 alpha, IL-beta, IL-6, and IL-8 production stimulated by S-27609 and imiquimod. Removal of HLA-DR+ or CD36+ monocytes also caused a significant reduction in S-27609- and imiquimod-induced IFN-alpha and TNF. Elimination of B cells, NK cells, and dendritic cells did not significantly reduce cytokine induction in response to S-27609. Thus, the cell population responsible for the majority of cytokine release in human PBMC in response to S-27609 and imiquimod is a E rosette-, CD14+, CD36+, HLA-DR+ monocyte.
Assuntos
Adjuvantes Imunológicos/farmacologia , Aminoquinolinas/farmacologia , Citocinas/biossíntese , Indutores de Interferon/farmacologia , Antígenos CD36/sangue , Antígenos HLA-DR/imunologia , Humanos , Imiquimode , Receptores de Lipopolissacarídeos/sangue , Monócitos/imunologiaRESUMO
The mechanism of action of imiquimod 5% cream applied topically to patients with genital warts was evaluated in a double-blind, placebo-controlled study. Imiquimod (16 patients) or placebo (three patients) was applied three times per week for up to 16 weeks. All imiquimod-treated patients had a > or =75% reduction in total wart area while only one of three placebo-treated patients had a similar reduction. Wart biopsies were taken at prestudy, week 6, and end of treatment. Polymerase chain reaction (PCR) for human papillomavirus (HPV) DNA and reverse transcriptase (RT)-PCR for messenger (m)RNAs were used to identify cytokines, cellular markers, viral gene products, and cell cycle markers in these biopsies. Treatment with imiquimod, an immune response modifier, stimulated significant increases in mRNA for interferon (IFN)-alpha, IFN-gamma and 2',5' oligoadenylate synthetase (2',5'-AS) as well as a tendency towards increases in tumor necrosis factor (TNF)-alpha and interleukin-12 p40. Significant increases in mRNA for CD4 and a trend toward increases in CD8 were also observed in imiquimod-treated patients, suggesting activation of a cell mediated immune response. Imiquimod administration was also associated with a significant decrease in viral load as measured by HPV DNA and L1 mRNA. The effects on HPV markers were accompanied by an apparent decrease in mRNA expression for markers of cell proliferation and an increase in mRNA for markers of keratinocyte differentiation and tumor suppressors.
Assuntos
Aminoquinolinas/uso terapêutico , Condiloma Acuminado/tratamento farmacológico , Doenças dos Genitais Femininos/tratamento farmacológico , Doenças dos Genitais Masculinos/tratamento farmacológico , Indutores de Interferon/uso terapêutico , Adolescente , Adulto , Antígenos CD/genética , Antígenos CD/metabolismo , Diferenciação Celular , Divisão Celular , Condiloma Acuminado/imunologia , Condiloma Acuminado/virologia , Citocinas/genética , Citocinas/metabolismo , Método Duplo-Cego , Feminino , Doenças dos Genitais Femininos/imunologia , Doenças dos Genitais Femininos/virologia , Doenças dos Genitais Masculinos/imunologia , Doenças dos Genitais Masculinos/virologia , Humanos , Imiquimode , Queratinócitos/patologia , Masculino , Pessoa de Meia-Idade , Papillomaviridae/genética , Papillomaviridae/isolamento & purificação , Papillomaviridae/fisiologia , Reação em Cadeia da Polimerase , RNA Mensageiro/metabolismo , Carga ViralRESUMO
Recently, a new class of immunomodulating agents, represented by the molecules imiquimod and R-842, has demonstrated potent antiviral and antitumor activities in animal models. In this study, another representative of this class, S-28463 (4-amino-2-ethoxymethyl-alpha,alpha-dimethyl-1H-imidazo[4,5-c]quinoline- 1- ethanol) was evaluated for its immunomodulating and antiviral activities. S-28463 induced IFN and other cytokines in vivo in mice, rats, monkeys and in vitro in human peripheral blood mononuclear cell cultures. S-28463 showed potent antiviral activity against herpes simplex virus-challenged guinea pigs when given subcutaneously, dermally, or intravaginally 24 h before infection. Antiviral activity in guinea pigs correlated with the induction of serum 2',5'-oligoadenylate synthetase activity. Thus, S-28463, like the other imidazoquinolines, demonstrates potent antiviral and immunomodulating effects in a number of models.