RESUMEN
We investigated the systemic immunotoxic potential of respiratory exposure to diesel exhaust particles (DEP) in this study. Female B6C3F1 mice (approximately 8 weeks old) were exposed to increasing concentrations of DEP intratracheally, 3 times every two weeks, and sacrificed 2 or 4 weeks after the first exposure. The systemic toxicity and immune status in mice were evaluated. Mice exposed to DEP (1 to 15 mg/kg) showed no significant changes in body, spleen, or liver weights. Lung weights were increased in the mice exposed to 15 mg/kg DEP for 2 or 4 weeks. Except for a decreased platelet count, no significant alterations occurred in hematological parameters following DEP exposure. The number of splenic anti-sheep red blood cell (sRBC) IgM antibody-forming cells (AFC) decreased following DEP exposure for 2 weeks. This effect was less severe following 4 weeks of exposure and was only evident in the high dose group. Exposure to DEP also resulted in a significant decrease in the absolute numbers and the percentages of total spleen cells for total, CD4(+), and CD8(+) T cells, while the numbers of B cells and total nucleated cells in spleen were not significantly changed. The proliferative response of splenocytes to the T-cell mitogen, concanavalin A (ConA), as well as their production of IL-2 and IFN-gamma, was decreased dose-dependently following exposure of mice to DEP for 2 weeks, whereas proliferation was not changed in response to anti-CD3 monoclonal antibody. In summary, short-term respiratory exposure of mice to DEP resulted in systemic immunosuppression with evidence of T cell-mediated and possibly macrophage-mediated mechanisms.
Asunto(s)
Inmunoglobulina M/biosíntesis , Terapia de Inmunosupresión , Bazo/efectos de los fármacos , Linfocitos T/efectos de los fármacos , Emisiones de Vehículos/toxicidad , Adyuvantes Inmunológicos , Animales , División Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Femenino , Exposición por Inhalación , Intubación Intratraqueal , Pulmón/efectos de los fármacos , Pulmón/patología , Ratones , Ratones Endogámicos , Tamaño de los Órganos/efectos de los fármacos , Bazo/inmunología , Linfocitos T/inmunologíaRESUMEN
A number of methods have been developed to assess the impact of a xenobiotic on the various components of the immune system. For risk analysis, it is necessary to determine what degree of chemically induced immune perturbation translates into altered host resistance. Natural killer (NK) cells play a pivotal role in the innate immune system with the ability to lyse cells infected with intracellular pathogens and certain tumors without previous exposure to the antigen. Spontaneous NK activity in B6C3F1 mice could be incrementally and consistently decreased by 20 to > or =80% by the intravenous administration of a range of dilutions of anti-asialo GM1 (AAGM1) antibody. The decrease in spontaneous NK activity following a single iv administration of AAGM1 antibody persisted for up to approximately 3 weeks when the initial suppression (e.g., 24 h after AAGM1 antibody injection) was almost 100%. Treatment with AAGM1, however, did not appear to perturb the function of other immune cells, based on results of the plaque assay, the mixed lymphocyte response, the cytotoxic T lymphocyte assay, the reticuloendothelial system clearance of sRBC assay, and the Streptococcus pneumoniae host resistance assay. Following a > or =80% decrease in spontaneous NK activity in mice, challenge with > or =1 x 10(3) B16F10 melanoma cells resulted in an increase in tumor burden based on the number of lung nodules. However, following challenge with 1 x 10(5) melanoma cells, a significant increase in tumor burden in mice was not observed until spontaneous NK activity had been decreased by > or =50-60%. Altered host resistance is a function not only of the magnitude of the decrease in NK activity but also of the magnitude of the challenge to the host.
Asunto(s)
Terapia de Inmunosupresión , Células Asesinas Naturales/inmunología , Animales , Anticuerpos/farmacología , Peso Corporal/efectos de los fármacos , Recuento de Células , Células Cultivadas , Cruzamientos Genéticos , Pruebas Inmunológicas de Citotoxicidad , Relación Dosis-Respuesta Inmunológica , Eritrocitos/inmunología , Gangliósido G(M1)/antagonistas & inhibidores , Gangliósido G(M1)/inmunología , Huésped Inmunocomprometido/inmunología , Inmunosupresores/farmacología , Células Asesinas Naturales/citología , Células Asesinas Naturales/efectos de los fármacos , Melanoma/inmunología , Melanoma/patología , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Trasplante de Neoplasias/inmunología , Tamaño de los Órganos/efectos de los fármacos , Bazo/citología , Bazo/inmunología , Streptococcus pneumoniae/inmunología , Streptococcus pneumoniae/patogenicidad , Linfocitos T/citología , Linfocitos T/inmunología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Chemical-induced allergy continues to be an important occupational health problem. Despite decades of investigation, the molecular mechanisms underlying chemical-induced hypersensitivity and irritancy remain unclear because of the complex interplay between properties of different chemicals and the immune system. In this study, gene expression induced by toluene diisocyanate (TDI, a primarily IgE-inducing sensitizer), oxazolone (OXA, a cell-mediated hypersensitivity inducing sensitizer), or nonanoic acid (NA, a non-sensitizing irritant) was investigated using gene arrays. Female BALB/c mice were dermally exposed on the ears once daily for 4 consecutive days. On day 5, the lymph nodes draining the exposure sites were collected and used for RNA extraction and subsequent hybridization to Affymetrix Mu6500 oligonucleotide arrays. Of the 6519 genes on the arrays, there were 44, 13, and 51 genes in the TDI-, OXA-, and NA-exposed samples, respectively, that displayed a minimum of twofold change in expression level relative to the vehicle control. There were 32, 19, and 19 genes that were differentially expressed (with a minimum of twofold change) between TDI and OXA, TDI and NA, OXA and NA, respectively. The differentially expressed genes include immune response-related genes, transcriptional factors, signal transducing molecules, and Expressed Sequence Tags. Based on the gene array results, candidate genes were further evaluated using RT-PCR. There was only about 47% concordance between the gene array and RT-PCR results.
Asunto(s)
Perfilación de la Expresión Génica , Expresión Génica/efectos de los fármacos , Irritantes/toxicidad , Análisis de Secuencia por Matrices de Oligonucleótidos , Animales , Ácidos Grasos/toxicidad , Femenino , Humanos , Hipersensibilidad/etiología , Inmunización , Ratones , Ratones Endogámicos BALB C , Enfermedades Profesionales/etiología , Oxazolona/toxicidad , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , 2,4-Diisocianato de Tolueno/toxicidadRESUMEN
Carbon tetrachloride (CCl(4)) is an environmental contaminant that has been detected in ambient air, seawater, surface-water and snow. The immunotoxic potential of CCl(4) was evaluated in female B6C3F1 mice. The animals were administered with CCl(4) daily for 14 days at doses of 50, 100, 500 or 1000 mg/kg body weight by gavage with corn oil as a vehicle. Exposure to CCl(4) resulted in an increase of liver weight but not the body weight and the weights of brain, spleen, lungs, thymus and kidneys. Exposure to CCl(4) produced minimal effect on differential hematological parameters; however, it produced a significant increase in serum glutamic-pyruvic transaminase (SGPT) levels in all dose groups while other serum chemistries showed sporadic increases, primarily at the dose level of 1000 mg/kg. Exposure to CCl(4) produced a decreased humoral immune response; the IgM antibody forming cell (AFC) response to sheep red blood cells (sRBC) was suppressed with the maximal decrease (45%) observed at the dose level of 1000 mg/kg. The IgM serum titer to sRBC was also reduced with a maximal decrease (54%) observed at the dose level of 500 mg/kg. Although exposure to CCl(4) had no effects on the mixed leukocyte response (MLR), cytotoxic T lymphocyte activity and natural killer (NK) cell activity, a decrease in both the absolute number and the percentage of CD4(+)CD8(-) at the dose level of 500 mg/kg was observed. The functional activity of the mononuclear phagocyte system was compromised as reflected by a decrease in the vascular clearance of (51)Cr-sRBC and a decrease in the uptake of (51)Cr-sRBC by the liver. Finally, in the two host resistance models evaluated, exposure to CCl(4) decreased host resistance to both Streptococcus pneumoniae and Listeria monocytogenes with greater susceptibility to the latter. Overall, these studies demonstrate that CCl(4) was immunosuppressive in female B6C3F1 mice.
Asunto(s)
Tetracloruro de Carbono/toxicidad , Listeria monocytogenes/patogenicidad , Listeriosis/inmunología , Infecciones Neumocócicas/inmunología , Streptococcus pneumoniae/patogenicidad , Alanina Transaminasa/sangre , Animales , Tetracloruro de Carbono/inmunología , División Celular , Radioisótopos de Cromo/química , Ensayo de Inmunoadsorción Enzimática , Recuento de Eritrocitos , Femenino , Citometría de Flujo , Hematócrito , Hemoglobinas/análisis , Inmunoglobulina M/análisis , Células Asesinas Naturales/inmunología , Recuento de Leucocitos , Subgrupos Linfocitarios , Ratones , Tamaño de los Órganos , Conteo por Cintilación , Ensayo de Placa ViralRESUMEN
Oxymetholone is a synthetic androgen, structurally related to testosterone. It is currently used to treat anemias, but has also been abused as a performance enhancing anabolic steroid by the sport community. Concern about its suspected immunomodulatory properties provided the incentive for a detailed investigation into its effects on the mammalian immune system. In this study, male B6C3F1 mice were treated for 14 d with oxymetholone (0, 50, 150, and 300 mg/kg) by gastric intubation, then evaluated for immunotoxicity using a panel of immunotoxicity assays. Except for an increasing trend in kidney and liver weights, and a dose-dependent increase in serum blood urea nitrogen levels, no other signs of systemic toxicity were observed. Bone marrow DNA synthesis was reduced, though this did not translate into alterations in myeloid or monocyte colony forming units. Spleen B and T cell numbers, antibody response to sheep red blood cells, proliferative response to both mitogen and immunoglobulin receptor immunogens, and NK cell activity were all unaltered in mice treated with oxymetholone. Peritoneal macrophage activity was also unaffected by oxymetholone treatment. A 38% decrease in the spleen cell mixed leukocyte response, and a 15% decrease in cytotoxic T cell activity, measured in the highest oxymetholone treatment group, indicate that cell-mediated immunity was impaired following exposure. This immunomodulation did not however, translate into a change in host resistance to Listeria monocytogenes.
Asunto(s)
Anabolizantes/toxicidad , Linfocitos B/efectos de los fármacos , Inmunidad Celular/efectos de los fármacos , Oximetolona/toxicidad , Bazo/efectos de los fármacos , Linfocitos T/efectos de los fármacos , Animales , Linfocitos B/metabolismo , Análisis Químico de la Sangre , Células de la Médula Ósea/citología , División Celular/efectos de los fármacos , Ciclofosfamida/farmacología , Hemoglobinas/análisis , Humanos , Inmunidad Innata/efectos de los fármacos , Inmunidad Innata/inmunología , Inmunoglobulina M/efectos de los fármacos , Inmunoglobulina M/metabolismo , Inmunosupresores/farmacología , Células Asesinas Naturales/efectos de los fármacos , Células Asesinas Naturales/metabolismo , Listeria monocytogenes/inmunología , Listeria monocytogenes/metabolismo , Prueba de Cultivo Mixto de Linfocitos , Macrófagos Peritoneales/efectos de los fármacos , Macrófagos Peritoneales/metabolismo , Masculino , Ratones , Ratones Endogámicos DBA , Distribución Aleatoria , Bazo/citología , Bazo/metabolismo , Linfocitos T/metabolismoRESUMEN
The immunotoxic potential of glycidol was evaluated in female B6C3F1 mice using a battery of functional assays and three host resistance models. Glycidol was administered to the animals by oral gavage as a solution in sterile distilled water daily for 14 days at doses of 25, 125 and 250 mg/kg. In tier I, we observed that glycidol exposure produced a dose-related decrease in splenocyte IgM antibody-forming cell response to sheep red blood cells (sRBC); the spleen natural killer (NK) cell activity was also decreased. A decrease in B cell proliferative responses to anti-IgM F(ab')2 and/or interleukin-4 (IL-4) was observed while the splenocyte proliferative responses to T cell mitogen ConA and B cell mitogen LPS were not affected. The splenocyte proliferative response to allogeneic cells as evaluated in the mixed leukocyte reaction (MLR) to DBA/2 spleen cells was not affected. In tier II, we found that exposure to glycidol decreased the number and percentage of B cells and the absolute number of CD4+ T cells in the spleen while the number of total T cells, CD8+ T cells and CD4+CD8+ T cells was not affected. The cytotoxic T lymphocyte (CTL) response to mitomycin C-treated P815 mastocytoma was not affected; the cytotoxic activity of peritoneal macrophages was not suppressed. Moreover, the host resistance to Listeria monocytogenes was not affected although a slight increase in host resistance to Streptococcus pneumoniae was observed. However, exposure to glycidol decreased host resistance to the B16F10 melanoma tumor model with the maximal tumor formation in lung observed in the high dose group. Overall, these dada support the finding that glycidol is an immunosuppressive agent in female B6C3F1 mice.
Asunto(s)
Células Productoras de Anticuerpos/efectos de los fármacos , Carcinógenos/toxicidad , Compuestos Epoxi/toxicidad , Inmunoglobulina M/inmunología , Inmunosupresores/toxicidad , Células Asesinas Naturales/efectos de los fármacos , Propanoles/toxicidad , Bazo/efectos de los fármacos , Animales , Formación de Anticuerpos/efectos de los fármacos , Linfocitos B/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Carcinógenos/administración & dosificación , Relación Dosis-Respuesta a Droga , Compuestos Epoxi/administración & dosificación , Femenino , Sistema Inmunológico/efectos de los fármacos , Inmunidad/efectos de los fármacos , Inmunidad Celular , Inmunosupresores/administración & dosificación , Intubación Gastrointestinal , Activación de Linfocitos/efectos de los fármacos , Ratones , Ratones Endogámicos , Tamaño de los Órganos/efectos de los fármacos , Propanoles/administración & dosificación , Bazo/patología , Pruebas de ToxicidadRESUMEN
Although the prevalence of IgE-mediated latex allergy has increased over the past decade, the circumstances which culminate in sensitization remain uncertain. The objective of these studies was to evaluate the role which sensitization route plays in the development of latex allergy using murine models representative of potential exposure routes by which health care workers (topical and respiratory) and spina bifida patients (subcutaneous) may be sensitized. BALB/c mice administered latex proteins by the subcutaneous, topical, intranasal, or intratracheal routes exhibited dose-responsive elevations in total IgE. In vitro splenocyte stimulation initially demonstrated specificity of the murine immune response to latex proteins. Subsequently, immunoblot analysis was used to compare latex-specific IgE production amongst sensitization routes. Immunoblots of IgE from subcutaneously sensitized mice demonstrated recognition of latex proteins with molecular weights near 14 kDa and 27 kDa. These protein sizes are consistent with the molecular weights of major latex allergens (Hev b 1 and Hev b 3), to which high percentages of spina bifida patients develop antibodies. Mice sensitized by intratracheal or topical administration exhibited combined IgE recognition of latex proteins near 14 kDa, 35 kDa, and 92 kDa. These molecular weights are similar to other latex allergens (Hev b 6, Hev b 2, and Hev b 4) commonly recognized by IgE of health care workers. Mice sensitized to latex proteins by topical, intranasal, or intratracheal exposures exhibited bronchoconstriction as evaluated by whole body plethysmography following respiratory challenge with latex proteins. Subcutaneously sensitized mice were unresponsive. These differences in latex-specific IgE immunoblot profiles and altered pulmonary function amongst the four different sensitization routes suggest that exposure routes leading to sensitization may play a role in determining the primary allergen(s), and the clinical manifestation of the allergic responses.
Asunto(s)
Alérgenos/administración & dosificación , Inmunoglobulina E/análisis , Hipersensibilidad al Látex/inmunología , Proteínas de Plantas/administración & dosificación , Goma/administración & dosificación , Alérgenos/inmunología , Animales , Pruebas de Provocación Bronquial , Broncoconstricción/efectos de los fármacos , Concanavalina A/farmacología , Modelos Animales de Enfermedad , Vías de Administración de Medicamentos , Femenino , Pulmón/efectos de los fármacos , Activación de Linfocitos , Ratones , Ratones Endogámicos BALB C , Peso Molecular , Proteínas de Plantas/inmunología , Pletismografía Total , Bazo/citología , Bazo/efectos de los fármacos , Bazo/inmunologíaRESUMEN
Thalidomide has been shown to have antiinflammatory and, more recently, immunomodulating properties, which are beneficial for the treatment of an ever-increasing list of immune related diseases. Although considerable knowledge regarding thalidomide s antiinflammatory properties has been acquired, relatively little is known about its immunomodulating properties in vivo. In this paper, a panel of immune assays was used to evaluate immunomodulation in female B6C3F1 mice treated intraperitoneally for 28 days with thalidomide (30, 100, or 150 mg/kg/day). Spleen antibody forming cell response was significantly enhanced by 37% in mice treated with 150 mg/kg/day, despite an 8% decrease in the percentage of Ig+ B cells. A significant stimulatory trend was observed for the cytotoxic T cell response across thalidomide treatment groups. An evaluation of the spleen leukocyte subpopulations revealed a 23% increase in the absolute number of CD8+ T cells in the 150 mg/kg treatment group and a 9 and 11% decrease in the absolute number of NK cells in both the 100 and 150 mg/kg thalidomide treatment groups, respectively. These findings demonstrate that, in addition to modulating spleen leukocyte numbers, thalidomide also stimulates murine humoral and cellular immune responses in vivo.
Asunto(s)
Inmunosupresores/farmacología , Bazo/efectos de los fármacos , Subgrupos de Linfocitos T/efectos de los fármacos , Linfocitos T Citotóxicos/efectos de los fármacos , Talidomida/farmacología , Animales , Peso Corporal/efectos de los fármacos , Recuento de Células/efectos de los fármacos , Femenino , Inmunoglobulina M/inmunología , Inmunosupresores/sangre , Inyecciones Intraperitoneales , Células Asesinas Naturales/inmunología , Ratones , Tamaño de los Órganos/efectos de los fármacos , Bazo/inmunología , Subgrupos de Linfocitos T/citología , Linfocitos T Citotóxicos/citología , Talidomida/sangreRESUMEN
The local lymph node assay (LLNA), as recommended by the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM), only allows for the use of CBA mice. The objective of these studies was to begin to assess the response of chemical sensitizers in the LLNA across six strains of female mice (C57BL/6, SJL/J, BALB/c, B6C3F1, DBA/2 and CBA). The moderate sensitizer alpha-hexylcinnamaldehyde (HCA) was chosen as the test chemical, while toluene diisocyanate (TDI) and 2,4-dinitrofluorobenzene (DNFB) were evaluated at single concentrations as positive controls. Draining lymph node cell proliferation following acetone exposure varied across strains. SJL mice had a significantly higher degree of proliferation with 2111 d.p.m./2 nodes. The remaining five strains demonstrated responses which ranged from 345 to 887 dpm/2 nodes. DBA/2, B6C3F1, BALB/c and CBA mice had essentially equal levels of lymph node proliferation following exposure to the three chemicals. While C57BL/6 mice gave similar results as CBA mice following DNFB and HCA administration, the LLNA response to TDI was considerably lower. SJL mice provided low stimulation indexes (SI) values for all three chemicals evaluated. Regardless of the level of LLNA response, all six mouse strains identified the sensitization potential of HCA, TDI or DNFB. Based on these studies, DBA/2, B6C3F1 and BALB/c mice are good choices for continued evaluation as additional mouse strains for use in the LLNA.
Asunto(s)
Ganglios Linfáticos/efectos de los fármacos , Acroleína/análogos & derivados , Acroleína/toxicidad , Animales , Dermatitis Alérgica por Contacto/patología , Dinitrofluorobenceno/toxicidad , Femenino , Ganglios Linfáticos/citología , Ratones , Ratones Endogámicos , Especificidad de la Especie , Estimulación Química , Timidina/metabolismo , 2,4-Diisocianato de Tolueno/toxicidadRESUMEN
Octamethylcyclotetrasiloxane, D4, is a low viscosity, silicone fluid consisting of four dimethyl-siloxy units ((CH3)2SiO)4 in a cyclic structure. It is primarily used as a building block in the industrial synthesis of long chain silicone polymers. The combination of D4 with decamethylcyclopentasiloxane (D5) is commonly referred to as cyclomethicone which has a wide range of applications as a formulation aid in personal care products. To extend the existing database regarding the biological activities of D4, a 28 day whole body vapor inhalation study was conducted using Fischer 344 rats at 0 (room air), 7, 20, 60, 180 and 540 ppm for 6 hours/day, 5 days/week. Parameters measured included body weights, organ weights, gross pathology, histopathology, serum chemistries, and urinalysis. In addition to these standard toxicological endpoints, the ability of D4 exposed animals to mount an IgM antibody response was evaluated by a splenic antibody forming cell (AFC) assay and a serum enzyme-linked immunosorbant assay (ELISA). The results of this 28-day inhalation study indicate that D4 exposure caused no adverse effects on body weight, food consumption, or urinalysis parameters. In addition, there were no exposure related histopathological alterations at any site for any exposure group. A statistically significant increase in liver weight and the liver to body weight ratio was observed in both male (180-540 ppm) and female (20-540 ppm) rats, which was not observed in the 14-day recovery group animals. There were no other significant organ weight changes. Although statistically significant changes were observed in several hematological and serum chemistry parameters in both the terminal and 14-day recovery animals, the changes were marginal and within the normal range of values for the rat. Under these experimental conditions, there were no alterations noted in immune system function at any of the D4 exposure levels.
Asunto(s)
Adyuvantes Inmunológicos/toxicidad , Células Productoras de Anticuerpos/efectos de los fármacos , Sistema Inmunológico/efectos de los fármacos , Hígado/efectos de los fármacos , Siloxanos/toxicidad , Adyuvantes Inmunológicos/química , Administración por Inhalación , Animales , Formación de Anticuerpos/efectos de los fármacos , Recuento de Células Sanguíneas/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayo de Inmunoadsorción Enzimática , Femenino , Inmunoglobulina M/análisis , Hígado/patología , Masculino , Tamaño de los Órganos/efectos de los fármacos , Ratas , Ratas Endogámicas F344 , Siloxanos/química , Bazo/efectos de los fármacos , Bazo/inmunología , Pruebas de ToxicidadRESUMEN
The plaque-forming cell (PFC) assay and enzyme-linked immunosorbent assay (ELISA) appear to have comparable sensitivity and reproducibility for measuring IgM antibody production in mice and rats immunized with sheep red blood cells (sRBCs). Both assays can be manipulated, with respect to the immunizing antigen (e.g., T-dependent vs T-independent antigen), to provide evidence as to which cell type(s) may be adversely affected by a given compound. However, the PFC assay has more utility in dissecting out the target cell(s) involved. Since both the PFC assay and the ELISA may be readily conducted in the rat, it is feasible to incorporate either of these assays into standard acute and repeat dose toxicology studies. This may be accomplished by inclusion of satellite groups in the study. However, it has been suggested that the primary antibody response to sRBCs, as measured by an ELISA, may also be evaluated in the main group of animals in a toxicology study without compromise to the integrity of other toxicological endpoints (e.g., hematology, clinical chemistry, histopathology). Both approaches will provide a more extensive delineation of the safety profile of a drug or chemical. The latter approach will also reduce the number of animals needed and the cost of the study.
Asunto(s)
Formación de Anticuerpos , Ensayo de Inmunoadsorción Enzimática/métodos , Técnica de Placa Hemolítica , Animales , Ensayo de Inmunoadsorción Enzimática/estadística & datos numéricos , Eritrocitos/inmunología , Estudios de Evaluación como Asunto , Técnica de Placa Hemolítica/estadística & datos numéricos , Humanos , Inmunización , Inmunoglobulina M/biosíntesis , Ratones , Ratas , Sensibilidad y Especificidad , Ovinos , Toxicología/métodosAsunto(s)
Hipersensibilidad Inmediata/inmunología , Hipersensibilidad al Látex/inmunología , Látex/inmunología , Administración Intranasal , Administración Tópica , Animales , Reacciones Cruzadas/inmunología , Femenino , Inmunoglobulina E/sangre , Inyecciones Subcutáneas , Látex/administración & dosificación , Ratones , Ratones EndogámicosRESUMEN
Patulin is a mycotoxin produced by many fungal species of the genera Penicillium, Aspergillus and Bryssochamys. Previous literature reports have suggested that patulin is toxic to the immune system. The studies presented were conducted to provide a comprehensive assessment of the effects of patulin on the immune system. Unlike previous reports, the doses of patulin used (0.08, 0.16, 0.32, 0.64, 1.28 and 2.56 mg/kg) were based on predicted human exposure levels. Female B6C3F1 mice were exposed orally to patulin for 28 days. Effects were not observed on final body weight or body weight gain. Relative weight of the liver, spleen, thymus, kidneys with adrenals, and lungs was not affected. Peripheral blood leucocyte and lymphocyte counts were decreased by approximately 30% in the two highest dose groups. The leucocyte differential was not altered. Total spleen cell, total T-cell (CD3+), helper T-cell (CD4+CD8-), B-cell (surface immunoglobulin+) and monocyte (MAC-3+) counts were not changed. Cytotoxic T-cell (CD8+CD4-) counts were increased 50% only by the highest dose. Natural killer cell (NK1.1+CD3-) and monocyte (MAC-1+) counts were increased 30% and 24%, respectively, only in the 0.08 mg/kg group. Humoral immune function as assessed by antibody-forming cell response and serum IgM titre to sheep erythrocytes, and cell-mediated immune function evaluated utilizing natural killer cell activity and the mixed lymphocyte reaction were not altered. Oral exposure to patulin for 28 days did not alter the ability of female B6C3F1 mice to mount either a cell-mediated or humoral immune response.
Asunto(s)
Carcinógenos/toxicidad , Patulina/toxicidad , Animales , Linfocitos B/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Eritrocitos/inmunología , Femenino , Inmunoglobulina M/biosíntesis , Células Asesinas Naturales/efectos de los fármacos , Recuento de Linfocitos/efectos de los fármacos , Prueba de Cultivo Mixto de Linfocitos , Ratones , Ratones Endogámicos , Tamaño de los Órganos/efectos de los fármacos , Ovinos/inmunología , Bazo/enzimología , Bazo/inmunología , Subgrupos de Linfocitos T/efectos de los fármacosRESUMEN
IL-6 has been characterized as a pleiotropic cytokine with multiple biologic activities, but its induction and role in asbestos diseases have not been studied. Asbestos fibers were found to stimulate IL-6 expression and secretion in pulmonary type II-like epithelial A549 cells as well as in normal human bronchial epithelial cells. IL-6 induction was dependent on the intracellular redox-oxidative state, since intracellular hydroxyl scavengers and N-acetylcysteine, a precursor of glutathione, abrogated IL-6 secretion by asbestos or H2O2. IL-6 induction paralleled increased DNA binding activity to the nuclear factor-kappa B (NF-kappa B)- and NF-IL-6-recognized sites in the IL-6 promoter. The NF-kappa B and NF-IL-6 DNA binding proteins were immunochemically characterized as a heterodimer p65/p50 and a homodimer C/EBP beta, respectively. Stimulation of DNA binding activity to the NF-kappa B and NF-IL-6 binding sites of the IL-6 promoter by asbestos or H2O2 were inhibited by tetramethylthiourea, a hydroxyl radical scavenger. The role of local IL-6 production in the pathophysiologic processes of fiber-induced lung disorders was examined. Although less active than fibroblast growth factor, human rIL-6 also stimulated lung fibroblast growth, as evidenced by increased [3H]thymidine incorporation. Furthermore, elevated IL-6 levels were found in bronchoalveolar lavage fluids from patients diagnosed with lung fibrosis and work-related histories of long term asbestos exposure. Taken together, the results suggest that asbestos-induced oxidative stress is involved in the activation of NF-kappa B and NF-IL-6 transcription factors, which recognize the IL-6 promoter. The resulting increase in IL-6 expression may be involved in both inflammatory and fibrotic processes in the lung.
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Asbesto Crocidolita/farmacología , Células Epiteliales/efectos de los fármacos , Células Epiteliales/inmunología , Interleucina-6/metabolismo , Pulmón/efectos de los fármacos , Pulmón/inmunología , Especies Reactivas de Oxígeno/fisiología , Adenocarcinoma Bronquioloalveolar , Líquido del Lavado Bronquioalveolar/química , Líquido del Lavado Bronquioalveolar/inmunología , Células Cultivadas , Electroforesis en Gel de Poliacrilamida , Células Epiteliales/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/inmunología , Humanos , Interleucina-6/genética , Pulmón/metabolismo , Neoplasias Pulmonares , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Oxidación-Reducción/efectos de los fármacos , Unión Proteica/efectos de los fármacos , Unión Proteica/inmunología , Células Tumorales CultivadasRESUMEN
2',3'-Dideoxyinosine (ddI) is a purine nucleoside analog currently being used for the treatment of HIV-positive individuals and patients with AIDS. Preliminary immunotoxicity studies have shown that a consequence of ddI treatment in female B6C3F1 mice is the inhibition of the humoral immune response. This effect was dose dependent in a range of 100 to 1000 mg/kg with a no observed adverse effect level of less than 100 mg/kg for a 28-day treatment period. These studies were undertaken to investigate the immune cell target of ddI and to determine the mechanism of this toxicity. B6C3F1 mice were treated with 1000 mg/kg/day by oral gavage for 28 days. The B lymphocyte was identified as the cellular target of ddI through separation-reconstitution experiments of the adherent and nonadherent cell populations and of the T and B lymphocyte populations. These studies revealed a deficit in the ability of the nonadherent cells from ddI-treated mice to mount a normal antibody response to sRBC. A further separation of the nonadherent cells into T and B cells revealed a decreased ability of ddI-treated B cells to develop specific humoral immunity. Additional studies were undertaken to determine the mechanism by which ddI is affecting the B cell. Surface marker analysis of splenocytes revealed no difference in the cell populations between vehicle- and ddI-treated mice. B cell proliferation was also unaffected as shown by incubation with either a polyclonal stimulator, lipopolysaccharide, or anti-IgM plus IL-4. These results indicate that the primary cellular target of ddI is the B lymphocyte.
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Subgrupos de Linfocitos B/efectos de los fármacos , Didanosina/toxicidad , Inmunoglobulina M/biosíntesis , Inmunoglobulina M/efectos de los fármacos , Animales , Subgrupos de Linfocitos B/inmunología , Subgrupos de Linfocitos B/metabolismo , Separación Celular , Cruzamientos Genéticos , Femenino , Inmunoglobulina G/biosíntesis , Inmunoglobulina G/efectos de los fármacos , Intubación Gastrointestinal , Activación de Linfocitos/efectos de los fármacos , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BLRESUMEN
2',3'-dideoxyinosine (ddI) is one of several purine analogues used for the treatment of HIV and the acquired immunodeficiency syndrome (AIDS). These nucleoside analogues are promising in their inhibition of viral reverse transcriptase and termination of DNA synthesis. However, each of these drugs has toxicity associated with its use. A previous immunotoxicological evaluation of 2',3'-dideoxyadenosine (ddA), the parent compound of ddI, showed that ddA suppresses humoral immunity. These studies were undertaken to determine the potential for immunotoxicity due to treatment with ddI. This evaluation included an assessment of innate and acquired immunity after exposure to ddI (100, 250, 500, and 1000 mg/kg/day) for 14, 28 or 180 days. There were no overt signs of toxicity related to treatment with ddI except for a decrease in body weight in the group treated with the highest dose of ddI for 180 days. Overall, 6 months of treatment with ddI showed minimal effects on specific organs with the exception of the spleen and thymus. ddI selectively targets the immune system, with assays that challenge humoral immunity being more affected than those testing cell-mediated immunity. Innate immunity was unaffected by ddI treatment. Cell-mediated immunity, as measured by proliferative response to allogeneic cells (MLR) and the T cell mitogen (Concanavalin A), was moderately suppressed. There were no ddI associated effects on NK function or macrophage function as measured by the vascular clearance rate and phagocytic uptake of the tissue macrophages. The most sensitive indicator of ddI-induced immunotoxicity is suppression of the response to the T-dependent antigen, sheep red blood cells (sRBC). The No Observable Adverse Effect Level (NOAEL) for toxicity to the immune system following 14 days of exposure to ddI is 250 mg/kg. A suppression of the humoral immune response was seen at the lowest dose tested after treatment for 28 and 180 days. Thus, the NOAEL for both of these treatment periods is below 100 mg/kg/day.
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Fármacos Anti-VIH/toxicidad , Didanosina/toxicidad , Sistema Inmunológico/efectos de los fármacos , Inhibidores de la Transcriptasa Inversa/toxicidad , Animales , Fármacos Anti-VIH/sangre , Peso Corporal/efectos de los fármacos , Células de la Médula Ósea/efectos de los fármacos , Células de la Médula Ósea/inmunología , División Celular/efectos de los fármacos , Didanosina/sangre , Femenino , Ratones , Ratones Endogámicos , Tamaño de los Órganos/efectos de los fármacos , Inhibidores de la Transcriptasa Inversa/sangre , Bazo/efectos de los fármacos , Bazo/inmunologíaRESUMEN
Gallium arsenide (GaAs) is an intermetallic compound used in the electronics industry as a semiconductor. Acute exposure of animals to GaAs suppresses various immune functions. We investigated the effects of GaAs on immunocompetency with emphasis on macrophages. Mice were given 12.5 to 200 mg/kg GaAs i.p., and immune parameters were examined 1 or 5 days later. Chemically exposed mice did not display alteration in spienic cellular composition. Despite this, primary in vitro humoral response to sheep red blood cells by GaAs-exposed mice was inhibited in a dose-dependent manner. The ability of 5-day vehicle- or 200 mg/kg GaAs-exposed splenic macrophages to induce interleukin-2 production by antigen-specific CD4+ helper T cell hybridomas stimulated with soluble protein antigens was assessed. GaAs-exposed macrophages were less competent in eliciting T cell responses to pigeon cytochrome c and pork insulin than vehicle-exposed cells. However, GaAs-exposed macrophages activated hen egg lysozyme- and chicken ovalbumin-specific T cells as efficiently as vehicle control cells. Also, suppressed processing of cytochrome c was not observed after a 1-day exposure. Chemical exposure did not alter the expression of major histocompatibility complex class II molecules on the macrophages or their activation of T cells by peptides, which do not require processing. Therefore, GaAs causes a time- and antigen-dependent defect in antigen processing that is essential for CD4+ T cell stimulation by splenic macrophages.
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Células Presentadoras de Antígenos/efectos de los fármacos , Arsenicales/farmacología , Linfocitos T CD4-Positivos/inmunología , Galio/farmacología , Activación de Linfocitos/efectos de los fármacos , Macrófagos/efectos de los fármacos , Animales , Antígenos de Histocompatibilidad Clase II/metabolismo , Hibridomas , Interleucina-2/metabolismo , Macrófagos/inmunología , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos DBA , Péptidos/inmunología , Bazo/citología , Bazo/efectos de los fármacos , Linfocitos T Colaboradores-Inductores/inmunología , Factores de TiempoRESUMEN
Current controversy regarding the effects of silicone gel mammary implants on the immune system has led to increased focus on the potential biological activity of silicone materials. Studies were undertaken in the B6C3F1 mouse to evaluate the immunotoxicological effects of the following components of a mammary gel prosthesis: polydimethylsiloxane fluid, silicone gel, elastomer shell and a polyurethane implant cover. Material was implanted subcutaneously (s.c.) for either 10 or 180 days. The only toxicological or immunological parameter which differed from control values was the natural killer (NK) cell activity in gel implanted mice. In these animals, basal NK activity was decreased. NK activity was comparably inhibited in female Fischer 344 rats implanted with silicone gel following short term (14 or 30 days) as well as chronic (1 year) exposure. The response was variable in both the rat and mouse. Host resistance to B16F10 melanoma in the mouse is known to be related to NK activity. Despite suppression of NK activity following gel implantation, host resistance was unaltered. Inhibition of NK activity by the administration of anti-asialo GM1 indicated that resistance was not adversely affected until NK activity was decreased by 40 to 50%. As with basal NK activity, augmented NK activity was inhibited in gel implanted rats when compared to controls. Administration of polyinosinic:polycytidylic acid to gel implanted rats resulted in an increase of approximately 65% in NK activity compared to gel implanted controls. This level of augmented NK activity was significantly less than the level of augmented NK activity in vehicle implanted animals where 100% enhancement in NK activity was noted. The results of these studies indicate that (1) NK cytolytic activity is altered in two animal models, the mouse and rat, although the results were variable, that (2) the level of suppression noted in the mouse is ineffective when compared to the level of suppression required to alter host resistance to B16F10 melanoma and that (3) the gel implanted animals exhibit a suppressed response to NK augmentation.
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Células Asesinas Naturales/efectos de los fármacos , Siliconas/farmacología , Animales , Femenino , Células Asesinas Naturales/inmunología , Melanoma Experimental/inmunología , Ratones , Ratas , Ratas Endogámicas F344RESUMEN
CI-959 is an orally effective inhibitor of cellular activation in both in vitro and animal models. To assess the effects of CI-959 on immune function, male Fischer 344 rats were evaluated for splenic T- and B-lymphocyte populations, antibody-forming cell response to sheep red blood cells (sRBC), concanavalin A and pokeweed mitogen-induced lymphocyte proliferation, Natural Killer cell activity, and reticuloendothelial system clearance of sRBC. Host resistance was measured in female B6C3F1 mice using Listeria monocytogenes, Streptococcus pneumonia, and B16F10 melanoma models. CI-959 was administered to both species of rodents at 25, 50, and 75 mg/kg/day for 14 days. A vehicle control and two positive controls (cyclophosphamide and dexamethasone) were run concurrently. CI-959 generally did not suppress immunological responses in rats at doses lower than those which also altered body weight gain and reduced spleen and thymus weights. Natural Killer cell activity was significantly reduced at 50 and 75 mg/kg CI-959. At 75 mg/kg rats also exhibited a reduction in ability to make anti-sRBC antibody. The number of T- and B-lymphocytes, proliferative response to mitogens, and macrophage activity of the reticuloendothelial system were not affected by CI-959. CI-959 also did not alter resistance of mice to Listeria monocytogenes, Streptococcus pneumoniae, or B16F10 melanoma cells. Based on these ex vivo and in vivo assays, the rodent immune system does not appear to be a sensitive or toxicologically important target for CI-959.