RESUMEN
BACKGROUND: Extreme sports events are increasing in popularity, particularly in mountainous areas throughout Great Britain. Emergency medical care for these events is usually provided by voluntary organisations, providing event side first aid and referring patients to nearby District General Hospitals. The Fort William Mountain Bike Race is part of the UCI World Cup Series: 173 competitors racing in cross country, downhill and 4X events. The Belford Hospital provides year round medical care for the Lochaber community, which frequently swells during the tourist season. The hospital has 8300 new attendances per annum, 35 patient reviews per 24 hrs. METHODS AND RESULTS: We have reviewed the impact of the event on the local hospital. In total 52 riders reported 61 injuries. The hospital treated 24q (14%) riders. Retrospective analysis of attendances has revealed 19 riders attended on race days, increasing attendees by up to 28%. 46% of injured riders were seen at the A &E department, 1 rider requiring admission for observation and 1 rider required inter-hospital transfer Injury patterns (knee 20%, hand/wrist 18% and shoulder 18%) were similar to other reported series. CONCLUSIONS: We believe that extreme sports events can have considerable impact on small district general hospitals. Additional triage and staffing resources should be utilised and event organisers should anticipate the additional problems they present to the local community. District General Hospitals continue to provide a substantial contribution to the provision of health care for extreme sports within the UK.
Asunto(s)
Traumatismos en Atletas/diagnóstico , Traumatismos en Atletas/epidemiología , Ciclismo/lesiones , Servicio de Urgencia en Hospital/estadística & datos numéricos , Adolescente , Adulto , Traumatismos en Atletas/terapia , Estudios de Casos y Controles , Femenino , Hospitales de Distrito , Hospitales Generales , Humanos , Incidencia , Puntaje de Gravedad del Traumatismo , Masculino , Estudios Retrospectivos , Escocia/epidemiologíaRESUMEN
The present studies demonstrate that the immunization of aged mice with Diphtheria toxoid in formulations containing unmethylated immunostimulatory CpG motifs, promotes the successful development of immune responses that are qualitatively and quantitatively comparable to those induced in young animals vaccinated in a similar manner. Aged mice given vaccines containing CpG oligodeoxynucleotides (ODNs) expressed primary and secondary systemic humoral immune responses having isotype profiles consistent with an enhancement in Th-1 type immunity. The ability to generate common mucosal immunity was also restored in aged animals given CpG ODN-containing vaccines. Dendritic cells (DCs) were determined to represent one of the cellular targets of CpG ODN activities in aged mice since restoration of immune function was observed when DCs from aged donors were pulsed with antigen and CpG ODNs, prior to injection into syngeneic young adult or aged recipients. Interestingly, antigen-pulsed DCs from young donors were fully capable of stimulating immune responses following their injection into syngeneic young adult or aged hosts, without a need for exposure to CpG ODNs. Although the mechanism(s) by which CpG DNA exerts its beneficial adjuvant effects on the aged immune system remains unclear, our findings suggest that the incorporation of CpG ODNs into vaccine formulations provided to the aged could prove useful in the development of more effective vaccines for the elderly.
Asunto(s)
Adyuvantes Inmunológicos , Envejecimiento/inmunología , Islas de CpG/inmunología , Oligodesoxirribonucleótidos/inmunología , Animales , Formación de Anticuerpos , Presentación de Antígeno/inmunología , Antígenos Bacterianos/inmunología , Células de la Médula Ósea/citología , Células de la Médula Ósea/inmunología , Calcitriol/inmunología , Células Dendríticas/inmunología , Vacuna contra Difteria, Tétanos y Tos Ferina/inmunología , Femenino , Vacunas contra Haemophilus/inmunología , Inmunoglobulina G/biosíntesis , Inmunofenotipificación , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Células TH1/inmunología , Vacunas Conjugadas/inmunologíaRESUMEN
Salmonella isolates that lack or overproduce DNA adenine methylase (Dam) elicited a cross-protective immune response to different Salmonella serovars. The protection afforded by the Salmonella enterica serovar Typhimurium Dam vaccine was greater than that elicited in mice that survived a virulent infection. S. enterica serovar Typhimurium Dam mutant strains exhibited enhanced sensitivity to mediators of innate immunity such as antimicrobial peptides, bile salts, and hydrogen peroxide. Also, S. enterica serovar Typhimurium Dam(-) vaccines were not immunosuppressive; unlike wild-type vaccines, they failed to induce increased nitric oxide levels and permitted a subsequent robust humoral response to diptheria toxoid antigen in infected mice. Dam mutant strains exhibited a low-grade persistence which, coupled with the nonimmunosuppression and the ectopic protein expression caused by altered levels of Dam, may provide an expanded source of potential antigens in vaccinated hosts.
Asunto(s)
Salmonelosis Animal/prevención & control , Salmonella/enzimología , Metiltransferasa de ADN de Sitio Específico (Adenina Especifica)/inmunología , Animales , Proteínas Bacterianas/biosíntesis , Reacciones Cruzadas , Tolerancia Inmunológica/inmunología , Ratones , Ratones Endogámicos BALB C , Membrana Mucosa/inmunología , Membrana Mucosa/microbiología , Mutagénesis , Salmonella/inmunología , Salmonella/patogenicidad , Vacunas contra la Salmonella/inmunología , Salmonella typhimurium/inmunología , Salmonella typhimurium/patogenicidad , Serotipificación , Metiltransferasa de ADN de Sitio Específico (Adenina Especifica)/genética , VirulenciaRESUMEN
Our previous studies have shown that the enzymatic activities of Neu-1, an endogenous sialidase encoded in the murine MHC, are involved in promoting IL-4 synthesis by naive CD4(+)T cells. Our present studies have characterized responsible sialoconjugate targets of Neu-1 and questioned possible biochemical mechanisms responsible for their regulatory influences on IL-4 gene expression. These studies determined that treatment of T cells with the naturally occurring ganglioside GM3 inhibited the production of IL-4 without affecting the production of IL-2. An analysis of IL-4-primed CD4(+)T cells further demonstrated that GM3 treatment specifically inhibited the restimulated production of IL-4, IL-5 and IL-13, without inhibiting the production of IL-2 and IFN-gamma. The inhibitory effects of GM3 could be overcome by treatment with thapsigargin or ionomycin, suggesting ganglioside regulation occurs upstream of activation-induced calcium mobilization. GM3 treatment attenuated the level of calcium influx following CD3epsilon crosslinking, and CD4(+)T cells from Neu-1-deficient B10.SM strain mice (neu-1(a)and IL-4-deficient) expressed reduced levels of intracellular calcium following activation. Our results indicate that activities by membrane gangliosides can influence the cytokine programs in CD4(+)T cells, possibly through the modulation of calcium responses induced by T cell activation.
Asunto(s)
Gangliósido G(M1)/metabolismo , Gangliósido G(M3)/metabolismo , Interleucina-13/biosíntesis , Interleucina-4/biosíntesis , Interleucina-5/biosíntesis , Linfocitos T/metabolismo , Animales , Anticuerpos Monoclonales/metabolismo , Complejo CD3/metabolismo , Linfocitos T CD4-Positivos/metabolismo , Calcio/metabolismo , Membrana Celular/metabolismo , Femenino , Gangliósido G(M1)/farmacología , Gangliósido G(M3)/farmacología , Líquido Intracelular/metabolismo , Ionomicina/farmacología , Ionóforos , Activación de Linfocitos/efectos de los fármacos , Ratones , Ratones Endogámicos C3H , Neuraminidasa/metabolismo , Complejo Receptor-CD3 del Antígeno de Linfocito T , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Acetato de Tetradecanoilforbol/farmacología , Células Tumorales CultivadasRESUMEN
The properties of various vaccine-adjuvant formulations that are capable of inducing both systemic and common mucosal immunity subsequent to their intradermal administration are described. Effective mucosal adjuvants, including bacterial toxins, chemical enhancers of cyclic AMP, and the active form of vitamin D3, all shared the ability to promote dendritic cell migration from the skin to Peyer's patches subsequent to antigen induced maturation. Our data suggests that skin dendritic cells may function as effective antigen presenting cells for the induction of mucosal immune responses, if microenvironmental conditions are appropriately manipulated subsequent to their stimulation by antigen.
Asunto(s)
Células Dendríticas/inmunología , Proteínas de Escherichia coli , Inmunidad Mucosa , Vacunas/administración & dosificación , Administración Tópica , Animales , Toxinas Bacterianas/inmunología , Movimiento Celular/inmunología , Colecalciferol/inmunología , Colecalciferol/metabolismo , Toxina del Cólera/inmunología , Colforsina/inmunología , AMP Cíclico/metabolismo , Enterotoxinas/inmunología , Ensayo de Inmunoadsorción Enzimática , Heces/química , Femenino , Inmunoglobulina A/análisis , Inmunoglobulina A/sangre , Inmunoglobulina G/sangre , Inyecciones Intradérmicas , Ratones , Ratones Endogámicos C3H , Ratas , Irrigación Terapéutica , Vacunas/inmunología , VaginaRESUMEN
Common mucosal immune responses were depressed in aged mice that were orally immunized with Haemophilus influenzae type b oligosaccharide conjugated to Diphtheria CRM197 protein (Hib-DT) vaccine using cholera toxin as the mucosal adjuvant. Both common mucosal and systemic humoral immune responses were also depressed in aged mice that were subcutaneously immunized with vaccine formulations containing Hib-DT plus 1alpha,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)). Dietary supplementation of aged mice with either the antioxidant vitamin E, or with known activators of the alpha isoform of the peroxisome proliferator activated receptor (PPAR-alpha) was capable of restoring their mucosal and systemic humoral immune responses to mature adult levels, by both the oral and subcutaneous routes of immunization. These data support a hypothesis that some aspects of immunosenescence are due to dysregulations in cellular functions, and are not due to any irreversible defects in cellular components of the immune system.
Asunto(s)
Envejecimiento/inmunología , Antioxidantes/administración & dosificación , Inmunidad Mucosa/efectos de los fármacos , Animales , Proteínas Bacterianas/administración & dosificación , Femenino , Vacunas contra Haemophilus/administración & dosificación , Tolerancia Inmunológica , Inmunoglobulina A/sangre , Inmunoglobulina A/metabolismo , Inmunoglobulina G/sangre , Inmunoglobulina G/metabolismo , Mucosa Intestinal/inmunología , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Modelos Biológicos , Proliferadores de Peroxisomas/administración & dosificación , Pirimidinas/administración & dosificación , Receptores Citoplasmáticos y Nucleares/metabolismo , Factores de Transcripción/metabolismo , Vagina/inmunologíaRESUMEN
Systemic and mucosal immune responses were effectively induced following the subcutaneous administration of Haemophilus influenzae type b oligosaccharide conjugated to diphtheria toxoid vaccine in a formulation containing the active form of vitamin D3. IgA and IgG antibodies with specificity for both the protein and oligosaccharide components of the vaccine were detectable in mucosal secretions following immunization. The IgA and IgG mucosal antibodies were produced locally, and were functional as demonstrated by their diphtheria toxin neutralizing activity. Our data suggests that subcutaneous tissues can effectively serve as effective antigen presenting sites for both mucosal and systemic immune responses to antigens administered in combination with vitamin D3.
Asunto(s)
Adyuvantes Inmunológicos/farmacología , Calcitriol/inmunología , Calcitriol/farmacología , Toxoide Diftérico/inmunología , Difteria/inmunología , Vacunas contra Haemophilus/inmunología , Inmunoglobulina A Secretora/biosíntesis , Inmunoglobulina G/biosíntesis , Animales , Especificidad de Anticuerpos , Antígenos Bacterianos/inmunología , Toxoide Diftérico/administración & dosificación , Epítopos/inmunología , Femenino , Vacunas contra Haemophilus/administración & dosificación , Células HeLa , Humanos , Inmunidad Mucosa/inmunología , Inmunización Pasiva , Inmunoglobulina A Secretora/sangre , Inmunoglobulina A Secretora/química , Inmunoglobulina G/sangre , Inmunoglobulina G/química , Inyecciones Subcutáneas , Ratones , Ratones Endogámicos C3H , Oligosacáridos/inmunología , Vacunación , Vacunas Conjugadas/administración & dosificación , Vacunas Conjugadas/inmunologíaRESUMEN
Alterations in transcription factor activities in aged mice may lead to the production of many inflammatory molecules in the absence of exogenous stimulation. Splenocytes from 22-month-old female C57BL/6 mice are dysregulated in their capacity to control the inducible nitric oxide synthase gene as a result of elevations in the endogenous levels and activity of interferon (IFN)-gamma. Splenocytes from aged mice produced high levels of IFN-gamma in vitro and active STAT-1 was found in nuclear extracts from these splenocytes. Administration to aged mice of neutralizing antibodies against IFN-gamma imposed appropriate regulation over nitric oxide production by stimulated splenocytes. Reestablishment of normal redox balance following dietary supplementation of aged mice with activators of the peroxisome proliferator-activated receptor alpha or the antioxidant alpha-tocopherol (vitamin E) restored appropriate regulation over both the production of IFN-gamma and the secretion of nitric oxide.
Asunto(s)
Envejecimiento/metabolismo , Interferón gamma/metabolismo , Óxido Nítrico Sintasa/metabolismo , Receptores Citoplasmáticos y Nucleares/agonistas , Bazo/enzimología , Factores de Transcripción/agonistas , Vitamina E/farmacología , Animales , Anticuerpos/inmunología , Núcleo Celular/metabolismo , Proteínas de Unión al ADN/metabolismo , Inducción Enzimática/efectos de los fármacos , Femenino , Interferón gamma/biosíntesis , Interferón gamma/inmunología , Interferón gamma/farmacología , Lipopolisacáridos/farmacología , Macrófagos/citología , Macrófagos/efectos de los fármacos , Macrófagos/enzimología , Macrófagos/metabolismo , Ratones , Ratones Endogámicos C57BL , Óxido Nítrico/metabolismo , Óxido Nítrico/orina , Óxido Nítrico Sintasa/genética , Óxido Nítrico Sintasa de Tipo II , Oxidación-Reducción , Pirimidinas/administración & dosificación , Pirimidinas/farmacología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores Citoplasmáticos y Nucleares/fisiología , Factor de Transcripción STAT1 , Bazo/citología , Bazo/efectos de los fármacos , Bazo/metabolismo , Transactivadores/metabolismo , Factores de Transcripción/fisiología , Vitamina E/administración & dosificaciónRESUMEN
OBJECTIVES: L-carnitine and dehydro-epiandrosterone (DHEA) independently promote mitochondrial energy metabolism. We therefore wondered if an age-related deficiency of L-carnitine or DHEA may account for the declining energy metabolism associated with age. METHODS: we evaluated serum levels of L-carnitine and the sulphated derivative of DHEA (DHEAS) in cross-sectional study of 216 healthy adults, aged 20-95. RESULTS: serum DHEAS levels declined, while total carnitine levels increased with age (P < 0.0001). Total and free carnitine and DHEAS levels were lower in women than men (P < 0.0001). Esterified/free (E/F) carnitine (inversely related to carnitine availability) increased with age in both sexes (P=0.012). CONCLUSION: reduced carnitine availability correlates with the age-related decline of DHEAS levels. These results are consistent with the hypothesis that decreased energy metabolism with age relates to DHEAS levels and carnitine availability.
Asunto(s)
Envejecimiento/sangre , Carnitina/sangre , Sulfato de Deshidroepiandrosterona/sangre , Adulto , Anciano , Anciano de 80 o más Años , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores SexualesRESUMEN
In aged mice, the redox-regulated transcription factor nuclear factor-kappaB (NF-kappaB) becomes constitutively active in many tissues, as well as in cells of the hematopoietic system. This oxidative stress-induced activity promotes the production of a number of pro-inflammatory cytokines, which can contribute to the pathology of many disease states associated with aging. The administration to aged mice of agents capable of activating the alpha isoform of the peroxisome proliferator-activated receptor (PPARalpha) was found to restore the cellular redox balance, evidenced by a lowering of tissue lipid peroxidation, an elimination of constitutively active NF-kappaB, and a loss in spontaneous inflammatory cytokine production. Aged animals bearing a null mutation in PPARalpha failed to elicit these changes following treatment with PPARalpha activators, but remained responsive to vitamin E supplementation. Aged C57BL/6 mice were found to express reduced transcript levels of PPARalpha and the peroxisome-associated genes acyl-CoA oxidase and catalase. Supplementation of these aged mice with PPARalpha activators or with vitamin E caused elevations in these transcripts to levels seen in young animals. Our results suggest that PPARalpha and the genes under its control play a role in the evolution of oxidative stress excesses observed in aging.
Asunto(s)
Envejecimiento/metabolismo , Citocinas/biosíntesis , FN-kappa B/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismo , Transducción de Señal , Factores de Transcripción/metabolismo , Acil-CoA Oxidasa , Animales , Secuencia de Bases , Catalasa/metabolismo , Cartilla de ADN , Sulfato de Deshidroepiandrosterona/farmacología , Mediadores de Inflamación/metabolismo , Peróxidos Lipídicos/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Obesidad/genética , Oxidación-Reducción , Oxidorreductasas/metabolismo , Fenotipo , Pirimidinas/farmacologíaRESUMEN
Synthetic forms of glucocorticoids (GCs) with high potency are widely used to treat a number of dermatological conditions having an inflammatory or autoimmune etiology. While GCs are generally effective in their ability to suppress inflammatory processes, their chronic use can lead to detrimental systemic side effects. In this report, we describe a method by which the localized antiinflammatory potential of the natural GC cortisol can be significantly augmented without increasing the risk of negative systemic effects. 11Beta-hydroxysteroid dehydrogenase (11beta-HSD) is a naturally occurring enzyme in the skin. 11Beta-HSD functionally converts biologically active 11-hydroxy GCs to their biologically inactive 11-keto metabolites, thereby limiting the ability of GCs to mediate antiinflammatory activities. By topically applying specific inhibitors of 11beta-HSD in conjunction with low doses of GCs, the antiinflammatory properties of cortisol can be significantly potentiated. It was observed that the generation of the effector phase of contact hypersensitivity (CH) responses could be suppressed by this combined treatment under conditions where the 11beta-HSD inhibitor alone, or cortisol alone were only minimally effective. Only the combined treatment was effective at inhibiting the progression of an ongoing CH response.
Asunto(s)
Antiinflamatorios/farmacología , Glucocorticoides/farmacología , Hidroxiesteroide Deshidrogenasas/antagonistas & inhibidores , Piel/efectos de los fármacos , Piel/enzimología , 11-beta-Hidroxiesteroide Deshidrogenasas , Administración Tópica , Animales , Antiinflamatorios/uso terapéutico , Dermatitis por Contacto/tratamiento farmacológico , Dermatitis por Contacto/enzimología , Dinitrofluorobenceno , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Femenino , Glucocorticoides/uso terapéutico , Ácido Glicirretínico/farmacología , Ácido Glicirretínico/uso terapéutico , Hidrocortisona/farmacología , Hidrocortisona/uso terapéutico , Hidroxiprogesteronas/farmacología , Hidroxiprogesteronas/uso terapéutico , Ratones , Ratones Endogámicos C3H , Piel/patologíaRESUMEN
The pathophysiology of many disease states observed in aged individuals has been linked to the dysregulated production of several pleiotropic cytokines. We have demonstrated that NF-kappa B, a major transcriptional regulator of these aberrantly expressed cytokines, exists in a constitutively activated state in cells obtained from the major lymphoid organs of aged animals. Therapeutic treatment with dietary antioxidants or with agents capable of activating the peroxisome proliferator-activated receptor (PPAR)-alpha was able to correct the abnormal nuclear NF-kappa B activity, reduce lipid peroxide levels, and eliminate the dysregulated expression of cytokines and other genes under NF-kappa B control. These results suggest that abnormal activation of NF-kappa B in aging contributes to the dysregulated expression of certain pleiotropic cytokines. Effective therapeutic regimens for aging and other inflammatory disease states might benefit from the administration of antioxidants or other agents which specifically activate PPAR-alpha.
Asunto(s)
Envejecimiento/inmunología , Envejecimiento/metabolismo , FN-kappa B/metabolismo , Envejecimiento/genética , Animales , Antioxidantes/farmacología , Secuencia de Bases , Citocinas/genética , Cartilla de ADN/genética , Femenino , Ratones , Ratones Endogámicos C57BL , Modelos Biológicos , Reacción en Cadena de la Polimerasa , Receptores Citoplasmáticos y Nucleares/metabolismo , Distribución Tisular , Factores de Transcripción/metabolismo , Transcripción GenéticaRESUMEN
Interleukin (IL)-12 or IL-4 produced early in an immune response directs the differentiation of naive antigen-activated CD4+ T cells down a Th1 or Th2 pathway. The NK1.1+ subset of T cells promptly produces IL-4 following activation in vivo. We demonstrate here that NK1.1+ T cells can be directly induced to produce IL-4 in vitro when activated under serum-free culture conditions. Platelet-derived growth factor in cell culture medium was inhibitory to the production of IL-4 by NK1.1+ T cells in vitro. Lymphocytes obtained from secondary lymphoid organs of aged mice produced greater quantities of IL-4 following stimulation than lymphocytes from mature adult animals. Aged mice expressed elevated percentages of NK1.1+ T cells in their secondary lymphoid organs and peripheral blood. While this cell type was responsible for the total early IL-4 produced by lymphocytes from mature adult mice, both NK1.1+ and memory phenotype (CD44high, CD45RBlow, NK1.1-) T cells from aged donors produced IL-4 following polyclonal T cell activation.
Asunto(s)
Envejecimiento/inmunología , Antígenos/inmunología , Linfocitos T CD4-Positivos/inmunología , Interleucina-4/biosíntesis , Activación de Linfocitos , Proteínas/inmunología , Actinas/genética , Animales , Antígenos Ly , Antígenos de Superficie , Becaplermina , Complejo CD3/inmunología , Células Cultivadas , Femenino , Receptores de Hialuranos/inmunología , Interleucina-2/biosíntesis , Interleucina-4/genética , Lectinas Tipo C , Antígenos Comunes de Leucocito/inmunología , Ratones , Ratones Endogámicos C57BL , Subfamilia B de Receptores Similares a Lectina de Células NK , Factor de Crecimiento Derivado de Plaquetas/farmacología , Proteínas Proto-Oncogénicas c-sis , ARN Mensajero , Receptores de Antígenos de Linfocitos T alfa-beta/inmunología , Bazo/citología , Bazo/inmunologíaRESUMEN
Constitutive expression of p35 and p40 IL-12 mRNA was detected in splenic macrophages isolated from aged mice. Macrophages were also implicated as the cell type responsible for the dysregulated IL-6 and tumor necrosis factor (TNF)-alpha commonly observed to be constitutively produced by lymphoid cells from aged donors. A role for IL-12 in the aging process was suggested when it was found that recombinant IL-12 (rIL-12) directly stimulated splenic CD5+ B cells to secrete IL-10, and both CD5+ and CD5- B cells could be directly induced to produce IL-6 in response to rIL-12. Furthermore, splenocytes from aged animals cultured in the presence of anti-IL-12 antibodies demonstrated a significant reduction in spontaneous IL-6, IL-10 and IFN-gamma production. Based on these observations it was concluded that IL-12 might be responsible for the dysregulated production of IL-10 and IFN-gamma known to occur in aged animals. Treatment of aged animals with low doses of dehydroepiandrosterone sulfate, previously established to be immunocorrective in immunosenescent animals, reduced the age-associated alterations in IL-12 mRNA and protein expression. The mechanisms responsible for the abnormal constitutive expression of inflammatory cytokines by the macrophages of aged animals may play an important afferent role in establishing the immunosenescent phenotype.
Asunto(s)
Envejecimiento/inmunología , Subgrupos de Linfocitos B/metabolismo , Antígenos CD5/análisis , Citocinas/genética , Interleucina-10/biosíntesis , Interleucina-12/farmacología , Interleucina-6/biosíntesis , Animales , Anticuerpos Monoclonales/farmacología , Subgrupos de Linfocitos B/efectos de los fármacos , Subgrupos de Linfocitos B/inmunología , Células Cultivadas , Citocinas/biosíntesis , Femenino , Interleucina-10/antagonistas & inhibidores , Interleucina-10/genética , Interleucina-12/inmunología , Interleucina-6/antagonistas & inhibidores , Interleucina-6/genética , Interfase/inmunología , Activación de Linfocitos/efectos de los fármacos , Macrófagos/citología , Macrófagos/metabolismo , Ratones , Ratones Endogámicos C57BL , ARN Mensajero/metabolismo , Bazo/citologíaRESUMEN
IL-4 is important in controlling the development of immune responses. Following activation with anti-CD3epsilon under serum-free conditions, splenocytes from most normal (neu-1b) mouse strains directly produced IL-4 and other T cell cytokines. However, splenic T cells from SM/J and B10.SM (H-2v, neu-1a) strain mice, deficient in neu-1 sialidase activity, failed to produce IL-4 but produced normal levels of IL-2 following activation. Moreover, sialidase-deficient mice produced markedly less IgE and IgG1 Abs following immunization with protein Ags than did mouse strains with normal neu-1 sialidase activity. Enriched T cells from neu-1a mice failed to be effectively primed with exogenous murine IL-4 to become IL-4-producing cells. Treatment of splenocytes or enriched T cells from neu-1a mice with bacterial sialidase prior to activation or IL-4 priming promoted their subsequent capacity to produce IL-4. In contrast, activation of T cells from neu-1b mice in the presence of a sialidase inhibitor almost completely blocked subsequent IL-4 production. The presence of IL-4 during priming enhanced T cell expression of neu-1-specific sialidase activity and increased the membrane expression of asialo-G(M1) compared with T cells activated without IL-4. These results suggest that T cell-associated neu-1 sialidase is required for early IL-4 production by splenic T cells and is involved in the IL-4 priming process of conventional T cells to become active IL-4 producers.
Asunto(s)
Regulación de la Expresión Génica/inmunología , Interleucina-4/biosíntesis , Interleucina-4/genética , Activación de Linfocitos/genética , Neuraminidasa/fisiología , Linfocitos T/enzimología , Animales , Células Cultivadas , Femenino , Gangliósido G(M1)/biosíntesis , Regulación de la Expresión Génica/efectos de los fármacos , Interleucina-4/farmacología , Activación de Linfocitos/efectos de los fármacos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Neuraminidasa/antagonistas & inhibidores , Neuraminidasa/farmacología , Bazo/citología , Linfocitos T/efectos de los fármacos , Linfocitos T/metabolismoRESUMEN
The results from the present study demonstrate that the innate defense mechanisms which control the progressive growth of Listeria monocytogenes in normal animals in vivo are dependent upon the active catabolism of endogenous glucocorticoids by the enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD). When 11 beta-HSD activity was pharmacologically inhibited in vivo, host susceptibility to progressive bacterial disease was markedly increased. Depressed natural resistance following 11 beta-HSD inhibition correlated with changes in the patterns of inducible cytokines by macrophages and T cells. Similar changes were observed when normal adult animals were treated with low doses of dexamethasone prior to experimental infection with Listeria.
Asunto(s)
Glucocorticoides/metabolismo , Hidroxiesteroide Deshidrogenasas/fisiología , Listeriosis/inmunología , 11-beta-Hidroxiesteroide Deshidrogenasas , Animales , Citocinas/biosíntesis , Susceptibilidad a Enfermedades , Femenino , Hidroxiesteroide Deshidrogenasas/antagonistas & inhibidores , Inmunidad Innata/efectos de los fármacos , Listeriosis/enzimología , Listeriosis/metabolismo , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BLRESUMEN
Elderly individuals often exhibit a poorer immune response and shorter duration of immunity to vaccines than younger persons. Improvement in vaccine response has been demonstrated when administering the hormone dehydroepiandrosterone sulfate (DHEAS) as an adjuvant in animal trials. Two separate, randomized double-blinded vaccine trials were therefore conducted using DHEAS as an oral adjuvant in individuals age 65 or older. Sixty-six individuals were randomized to DHEAS, 50 mg po bid for 4 days, or a placebo capsule. Tetanus vaccination was given immediately before the fifth dose. At entry the level of protective antibody was age-dependent (P = 0.009), and by 28 days post-vaccination most individuals had protective levels of antibody, with no difference noted between treatment groups. In the second study, 67 individuals received placebo capsules or DHEAS immediately before and 24 h after influenza vaccination. The number of individuals who developed protective titers (> or = 1:40) was not different in the two groups. The mean log increase in HAI response was greater in the DHEAS group to all three vaccine components, although this did not achieve significance. Minimal side-effects of DHEAS administration were noted. Given the trend toward improved response in the elderly to influenza, larger trials using DHEA as an adjuvant in vaccines that are neoantigens may be indicated.
Asunto(s)
Adyuvantes Inmunológicos/administración & dosificación , Sulfato de Deshidroepiandrosterona/inmunología , Vacunas contra la Influenza/inmunología , Toxoide Tetánico/inmunología , Administración Oral , Anciano , Anciano de 80 o más Años , Anticuerpos Antibacterianos/biosíntesis , Anticuerpos Antibacterianos/sangre , Anticuerpos Antivirales/biosíntesis , Anticuerpos Antivirales/sangre , Sulfato de Deshidroepiandrosterona/administración & dosificación , Sulfato de Deshidroepiandrosterona/sangre , Método Doble Ciego , Femenino , Humanos , Vacunas contra la Influenza/efectos adversos , Masculino , Toxoide Tetánico/efectos adversosRESUMEN
The immunoregulatory effects of glucocorticoids (GCS) are linked to their capacity to alter the production of various species of cytokines associated with immune and inflammatory processes. The present study determined that the influences of GCS within particular lymphoid organs vary, depending on the specific activity of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) within the tissue. This enzyme converts active GCS to inactive metabolites and was found to display greater activity in peripheral than in mucosal lymphoid organs. A direct correlation was found between 11 beta-HSD activity and the preferential production of type 1 cytokines by T-cells residing within certain lymphoid organs. It was established that lymphoid organ 11 beta-HSD was localized in the immobile stromal cell components. Inhibition of 11 beta-HSD activity in vivo reduced type 1 and enhanced type 2 cytokine production by activated T-cells, and it also depressed the ability of animals to generate contact hypersensitivity responses. We conclude that GCS levels can be controlled within lymphoid organs through oxidative inactivation by 11 beta-HSD. GCS action is, therefore, dependent on tissue levels of 11 beta-HSD activity, the number of GCS receptors in a responsive cell, and the concentration of circulating GCS.
Asunto(s)
Glucocorticoides/metabolismo , Hidroxiesteroide Deshidrogenasas/fisiología , Tejido Linfoide/enzimología , 11-beta-Hidroxiesteroide Deshidrogenasas , Animales , Citocinas/biosíntesis , Femenino , Isoenzimas/metabolismo , Hígado/enzimología , Activación de Linfocitos , Ratones , Ratones Endogámicos C3H , Células del Estroma/enzimología , Linfocitos T/metabolismo , Linfocitos T/fisiologíaRESUMEN
Peripheral lymphoid cells isolated from the spleens and peritoneal cavities of aged mice were found to constitutively secrete the multifunctional cytokine interleukin (IL)-10 when cultured in vitro. B-Lymphocytes were implicated as the cell type responsible. Abnormal expression of this cytokine was also detected in vivo because high levels of mRNA for IL-10 were present in splenocytes freshly isolated from aged animals. In addition to the spontaneous secretion of IL-10, lymphoid cells from aged donors were hyperresponsive to exogenous stimulation with endotoxin, producing exaggerated quantities of both IL-10 and IL-6 in culture. Treatment of aged animals with dehydroepiandrosterone sulfate (DHEAS), a natural steroid, reversed the age-associated alterations in cytokine production, rendering the treated mice quite similar to mature adult controls. DHEAS treatment of aged mice also resulted in a lowering in the number of B1 cells present in the peritoneal cavity and also reduced the titers of circulating autoantibodies specific for phosphatidylcholine (PtC). Based on its wide range of biologic activities, a dysregulation in the mechanisms that control IL-10 production could be a major contributor to immunosenescence. The ability of DHEAS treatment to restore normal control over the expression of IL-10 may explain how this steroid enhances immunocompetence in aged animals.
Asunto(s)
Envejecimiento/inmunología , Sulfato de Deshidroepiandrosterona/farmacología , Deshidroepiandrosterona/deficiencia , Interleucina-10/biosíntesis , Animales , Autoanticuerpos/sangre , Linfocitos B/metabolismo , Femenino , Ratones , Ratones Endogámicos CBARESUMEN
The study described in this report demonstrates that peripheral lymph nodes draining nonmucosal tissues can effectively serve as induction sites for the establishment of common mucosal immunity if the microenvironmental conditions are altered to mimic those normally present within mucosa-associated lymphoid tissues (e.g., Peyer's patches). Lymph node lymphocytes exposed in situ to the immunomodulatory influences of the hormone 1 alpha, 25-dihydroxy vitamin D 3 were found to produce less gamma interferon and interleukin-2 (IL-2) and far more IL-4, IL-5 and IL-10 than lymphocytes from control animals. When couples with vaccination with hepatitis B surface antigen (HBsAg), the hormone, immunomodulated switch from a peripheral lymph node phenotype to a Peyer's patch-like pattern promoted the induction of both a systemic and a common mucosal immune response. This was determined by the observed increased concentrations of serum anti-HBsAg antibody and by finding that anti-HBsAg secretory antibodies were detectable in urogenital, lachrymal, fecal and oral secretions only in the hormone-treated animals. In addition, specific antibody-secreting cells were detectable in the lamina propria of the lungs and small intestines of the hormone-treated animals subsequent to vaccination, indicating that the homing properties of antigen-specific B cells were being affected by the treatment procedure. The humoral and mucosal immune responses were further augmented if both 1 alpha, 25-dihydroxy vitamin D 3 and dehydroepiandrosterone were used together as hormonal immunomodulators. This novel immunization technique may afford new opportunities to effectively intervene in sexually transmitted diseases and other diseases caused by mucosal pathogens.