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1.
PLoS One ; 15(3): e0230668, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32208448

RESUMEN

The maintenance and propagation of complex mixtures of cells in vitro in the form of native organs or engineered organoids has contributed to understanding mechanisms of cell and organ development and function which can be translated into therapeutic benefits. For example, allogeneic cultured postnatal human thymus tissue has been shown to support production of naïve recipient T cells when transplanted into patients with complete DiGeorge anomaly and other genetic defects that result in congenital lack of a thymus. Patients receiving such transplants typically exhibit reversal of their immunodeficiency and normalization of their peripheral blood T cell receptor V-beta repertoire, with long-term survival. This study was designed to assess the histopathologic changes that occur in postnatal human thymus slices when cultured according to protocols used for transplanted tissues. Results showed that as thymic organ cultures progressed from days 0 through 21, slices developed increasing amounts of necrosis, increasing condensation of thymic epithelium, and decreasing numbers of residual T cells. The architecture of the thymic epithelial network remained generally well-preserved throughout the 21 days of culture, with focal expression of cytokeratin 14, a putative biomarker of thymic epithelial cells with long-term organ-repopulating potential. All organ slices derived from the same donor thymus closely resembled one another, with minor differences in size, shape, and relative content of cortex versus medulla. Similarly, slices derived from different donors showed similar histopathologic characteristics when examined at the same culture time point. Taken together, these results demonstrate that diagnostic criteria based on structural features of the tissue identifiable via hematoxylin and eosin staining and cytokeratin immunohistochemistry can be used to evaluate the quality of slices transplanted into patients with congenital athymia.

3.
PLoS One ; 14(2): e0210663, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30759098

RESUMEN

While exposure to radiation can be lifesaving in certain settings, it can also potentially result in long-lasting adverse effects, particularly to hematopoietic and immune cells. This study investigated hematopoietic recovery and immune function in rhesus macaques Cross-sectionally (at a single time point) 2 to 5 years after exposure to a single large dose (6.5 to 8.4 Gray) of total body radiation (TBI) derived from linear accelerator-derived photons (2 MeV, 80 cGy/minute) or Cobalt 60-derived gamma irradiation (60 cGy/min). Hematopoietic recovery was assessed through measurement of complete blood counts, lymphocyte subpopulation analysis, and thymus function assessment. Capacity to mount specific antibody responses against rabies, Streptococcus pneumoniae, and tetanus antigens was determined 2 years after TBI. Irradiated macaques showed increased white blood cells, decreased platelets, and decreased frequencies of peripheral blood T cells. Effects of prior radiation on production and export of new T cells by the thymus was dependent on age at the time of analysis, with evidence of interaction with radiation dose for CD8+ T cells. Irradiated and control animals mounted similar mean antibody responses to proteins from tetanus and rabies and to 10 of 11 serotype-specific pneumococcal polysaccharides. However, irradiated animals uniformly failed to make antibodies against polysaccharides from serotype 5 pneumococci, in contrast to the robust responses of non-irradiated controls. Trends toward decreased serum levels of anti-tetanus IgM and slower peak antibody responses to rabies were also observed. Taken together, these data show that dose-related changes in peripheral blood cells and immune responses to both novel and recall antigens can be detected 2 to 5 years after exposure to whole body radiation. Longer term follow-up data on this cohort and independent validation will be helpful to determine whether these changes persist or whether additional changes become evident with increasing time since radiation, particularly as animals begin to develop aging-related changes in immune function.


Asunto(s)
Rayos gamma/efectos adversos , Sistema Hematopoyético/efectos de la radiación , Inmunidad/efectos de la radiación , Irradiación Corporal Total/efectos adversos , Adulto , Animales , Formación de Anticuerpos/efectos de la radiación , Recuento de Células Sanguíneas , Relación Dosis-Respuesta en la Radiación , Hematopoyesis/efectos de la radiación , Humanos , Subgrupos Linfocitarios/efectos de la radiación , Macaca mulatta , Masculino , Traumatismos Experimentales por Radiación/etiología , Linfocitos T/efectos de la radiación , Timo/efectos de la radiación
4.
Nat Microbiol ; 3(12): 1441-1450, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30374168

RESUMEN

Resource limitation is a fundamental factor governing the composition and function of ecological communities. However, the role of resource supply in structuring the intestinal microbiome has not been established and represents a challenge for mammals that rely on microbial symbionts for digestion: too little supply might starve the microbiome while too much might starve the host. We present evidence that microbiota occupy a habitat that is limited in total nitrogen supply within the large intestines of 30 mammal species. Lowering dietary protein levels in mice reduced their faecal concentrations of bacteria. A gradient of stoichiometry along the length of the gut was consistent with the hypothesis that intestinal nitrogen limitation results from host absorption of dietary nutrients. Nitrogen availability is also likely to be shaped by host-microbe interactions: levels of host-secreted nitrogen were altered in germ-free mice and when bacterial loads were reduced via experimental antibiotic treatment. Single-cell spectrometry revealed that members of the phylum Bacteroidetes consumed nitrogen in the large intestine more readily than other commensal taxa did. Our findings support a model where nitrogen limitation arises from preferential host use of dietary nutrients. We speculate that this resource limitation could enable hosts to regulate microbial communities in the large intestine. Commensal microbiota may have adapted to nitrogen-limited settings, suggesting one reason why excess dietary protein has been associated with degraded gut-microbial ecosystems.


Asunto(s)
Bacterias/metabolismo , Microbioma Gastrointestinal/fisiología , Intestino Grueso/metabolismo , Intestino Grueso/microbiología , Mamíferos/microbiología , Nitrógeno/metabolismo , Animales , Bacterias/clasificación , Bacterias/genética , Bacterias/aislamiento & purificación , Carbono/metabolismo , Dieta , Proteínas en la Dieta , Heces/microbiología , Interacciones Microbiota-Huesped/fisiología , Ratones , ARN Ribosómico 16S/genética , Simbiosis
5.
Vaccine ; 36(45): 6650-6659, 2018 10 29.
Artículo en Inglés | MEDLINE | ID: mdl-30274868

RESUMEN

The objective of this study was to evaluate effects of whole body radiation exposure early in life on influenza vaccination immune responses much later in life. A total of 292 volunteers recruited from the cohort members of ongoing Adult Health Study (AHS) of Japanese atomic bomb (A-bomb) survivors completed this observational study spanning two influenza seasons (2011-2012 and 2012-2013). Peripheral blood samples were collected prior to and three weeks after vaccination. Serum hemagglutination inhibition (HAI) antibody titers were measured as well as concentrations of 25 cytokines and chemokines in culture supernatant from peripheral blood mononuclear cells, with and without in vitro stimulation with influenza vaccine. We found that influenza vaccination modestly enhanced serum HAI titers in this unique cohort of elderly subjects, with seroprotection ranging from 18 to 48% for specific antigen/season combinations. Twelve percent of subjects were seroprotected against all three vaccine antigens post-vaccination. Males were generally more likely to be seroprotected for one or more antigens post-vaccination, with no differences in vaccine responses based on age at vaccination or radiation exposure in early life. These results show that early life exposure to ionizing radiation does not prevent responses of elderly A-bomb survivors to seasonal influenza vaccine.


Asunto(s)
Vacunas contra la Influenza/uso terapéutico , Radiación Ionizante , Anciano , Anciano de 80 o más Años , Anticuerpos Antivirales/inmunología , Quimiocinas/metabolismo , Citocinas/metabolismo , Femenino , Pruebas de Inhibición de Hemaglutinación , Humanos , Subtipo H1N1 del Virus de la Influenza A , Vacunas contra la Influenza/inmunología , Gripe Humana/inmunología , Gripe Humana/prevención & control , Masculino , Factores Sexuales
6.
Radiat Res ; 187(5): 589-598, 2017 05.
Artículo en Inglés | MEDLINE | ID: mdl-28319462

RESUMEN

The thymus is essential for proper development and maintenance of a T-cell repertoire that can respond to newly encountered antigens, but its function can be adversely affected by internal factors such as pregnancy and normal aging or by external stimuli such as stress, infection, chemotherapy and ionizing radiation. We have utilized a unique archive of thymus tissues, obtained from 165 individuals, exposed to the 1945 atomic bomb blast in Hiroshima, to study the long-term effects of receiving up to ∼3 Gy dose of ionizing radiation on human thymus function. A detailed morphometric analysis of thymus activity and architecture in these subjects at the time of their natural deaths was performed using bright-field immunohistochemistry and dual-color immunofluorescence and compared to a separate cohort of nonexposed control subjects. After adjusting for age-related effects, increased hallmarks of thymic involution were observed histologically in individuals exposed to either low (5-200 mGy) or moderate-to-high (>200 mGy) doses of ionizing radiation compared to unirradiated individuals (<5 mGy). Sex-related differences were seen when the analysis was restricted to individuals under 60 years of attained age at sample collection, but were not observed when comparing across the entire age range. This indicates that while females undergo slower involution than males, they ultimately attain similar phenotypes. These findings suggest that even low-dose-radiation exposure can accelerate thymic aging, with decreased thymopoiesis relative to nonexposed controls evident years after exposure. These data were used to develop a model that can predict thymic function during normal aging or in individuals therapeutically or accidentally exposed to radiation.


Asunto(s)
Envejecimiento/patología , Enfermedades Linfáticas/mortalidad , Enfermedades Linfáticas/patología , Exposición a la Radiación/estadística & datos numéricos , Traumatismos por Radiación/mortalidad , Traumatismos por Radiación/patología , Timo/patología , Distribución por Edad , Humanos , Incidencia , Japón/epidemiología , Estudios Longitudinales , Enfermedades Linfáticas/fisiopatología , Dosis de Radiación , Traumatismos por Radiación/fisiopatología , Radiación Ionizante , Factores de Riesgo , Distribución por Sexo , Tasa de Supervivencia , Sobrevivientes/estadística & datos numéricos , Timo/fisiopatología , Timo/efectos de la radiación
7.
Cell Rep ; 17(5): 1330-1343, 2016 10 25.
Artículo en Inglés | MEDLINE | ID: mdl-27783947

RESUMEN

Normal dynamics between microbiota and dendritic cells (DCs) support modest numbers of T cells, yet these do not cause inflammation. The DCs that induce inflammatory T cells and the signals that drive this process remain unclear. Here, we demonstrate that small intestine DCs lacking the signaling attenuator A20 induce inflammatory T cells and that the signals perceived and antigen-presenting cell (APC) functions are unique for different DC subsets. Thus, although CD103+CD11b- DCs exclusively instruct IFNγ+ T cells, CD103+CD11b+ DCs exclusively instruct IL-17+ T cells. Surprisingly, APC functions of both DC subsets are upregulated in a MyD88-independent fashion. In contrast, CD103-CD11b+ DCs instruct both IFNγ+ and IL-17+ T cells, and only the IL-17-inducing APC functions require MyD88. In disease pathogenesis, both CD103-CD11b+ and CD103+CD11b+ DCs expand pathologic Th17 cells. Thus, in disease pathogenesis, specific DCs instruct specific inflammatory T cells.


Asunto(s)
Células Dendríticas/inmunología , Inflamación/patología , Intestinos/patología , Factor 88 de Diferenciación Mieloide/metabolismo , Células TH1/inmunología , Células Th17/inmunología , Animales , Células Presentadoras de Antígenos/metabolismo , Antígenos CD/metabolismo , Citocinas/genética , Citocinas/metabolismo , Microbioma Gastrointestinal , Regulación de la Expresión Génica , Humanos , Interleucina-17/metabolismo , Mucosa Intestinal , Ratones , Ratones Transgénicos , Fenotipo
9.
PLoS One ; 11(4): e0152764, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27045690

RESUMEN

Studies in transgenic murine models have provided insight into the complexity underlying inflammatory bowel disease (IBD), a disease hypothesized to result from an injurious immune response against intestinal microbiota. We recently developed a mouse model of IBD that phenotypically and histologically resembles human childhood-onset ulcerative colitis (UC), using mice that are genetically modified to be deficient in the cytokines TNF and IL-10 ("T/I" mice). Here we report the effects of early life onset of colon inflammation on growth and reproductive performance of T/I mice. T/I dams with colitis often failed to get pregnant or had small litters with pups that failed to thrive. Production was optimized by breeding double homozygous mutant T/I males to females homozygous mutant for TNF deficiency and heterozygous for deficiency of IL-10 ("T/I-het" dams) that were not susceptible to spontaneous colon inflammation. When born to healthy (T/I-het) dams, T/I pups initially gained weight similarly to wild type (WT) pups and to their non-colitis-susceptible T/I-het littermates. However, their growth curves diverged between 8 and 13 weeks, when most T/I mice had developed moderate to severe colitis. The observed growth failure in T/I mice occurred despite a significant increase in their food consumption and in the absence of protein loss in the stool. This was not due to TNF-induced anorexia or altered food consumption due to elevated leptin levels. Metabolic studies demonstrated increased consumption of oxygen and water and increased production of heat and CO2 in T/I mice compared to their T/I-het littermates, without differences in motor activity. Based on the clinical similarities of this early life onset model of IBD in T/I mice to human IBD, these results suggest that mechanisms previously hypothesized to explain growth failure in children with IBD require re-evaluation. The T/I mouse model may be useful for further investigation of such mechanisms and for development of therapies to prevent reproductive complications and/or growth failure in humans with IBD.


Asunto(s)
Modelos Animales de Enfermedad , Enfermedades Inflamatorias del Intestino/fisiopatología , Reproducción , Animales , Ratones
10.
J Histochem Cytochem ; 64(2): 112-24, 2016 02.
Artículo en Inglés | MEDLINE | ID: mdl-26392518

RESUMEN

Performance of immunofluorescence staining on archival formalin-fixed paraffin-embedded human tissues is generally not considered to be feasible, primarily due to problems with tissue quality and autofluorescence. We report the development and application of procedures that allowed for the study of a unique archive of thymus tissues derived from autopsies of individuals exposed to atomic bomb radiation in Hiroshima, Japan in 1945. Multiple independent treatments were used to minimize autofluorescence and maximize fluorescent antibody signals. Treatments with NH3/EtOH and Sudan Black B were particularly useful in decreasing autofluorescent moieties present in the tissue. Deconvolution microscopy was used to further enhance the signal-to-noise ratios. Together, these techniques provide high-quality single- and dual-color fluorescent images with low background and high contrast from paraffin blocks of thymus tissue that were prepared up to 60 years ago. The resulting high-quality images allow the application of a variety of image analyses to thymus tissues that previously were not accessible. Whereas the procedures presented remain to be tested for other tissue types and archival conditions, the approach described may facilitate greater utilization of older paraffin block archives for modern immunofluorescence studies.


Asunto(s)
Técnica del Anticuerpo Fluorescente/métodos , Adhesión en Parafina , Timo/ultraestructura , Fijación del Tejido , Adolescente , Adulto , Compuestos Azo/química , Colorantes/química , Formaldehído/química , Humanos , Microscopía Fluorescente/métodos , Persona de Mediana Edad , Naftalenos/química , Imagen Óptica , Parafina/química , Adhesión en Parafina/métodos , Fijación del Tejido/métodos , Adulto Joven
11.
PLoS Negl Trop Dis ; 9(9): e0004046, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-26393347

RESUMEN

Buruli ulcer, an emerging tropical disease caused by Mycobacterium ulcerans (MU), is characterized by disfiguring skin necrosis and high morbidity. Relatively little is understood about the mode of transmission, pathogenesis, or host immune responses to MU infection. Due to significant reduction in quality of life for patients with extensive tissue scarring, and that a disproportionately high percentage of those affected are disadvantaged children, a Buruli ulcer vaccine would be greatly beneficial to the worldwide community. Previous studies have shown that mice inoculated with either M. bovis bacille Calmette-Guérin (BCG) or a DNA vaccine encoding the M. ulcerans mycolyl transferase, Ag85A (MU-Ag85A), are transiently protected against pathology caused by intradermal challenge with MU. Building upon this principle, we have generated quality-controlled, live-recombinant strains of BCG and M. smegmatis which express the immunodominant MU Ag85A. Priming with rBCG MU-Ag85A followed by an M. smegmatis MU-Ag85A boost strongly induced murine antigen-specific CD4+ T cells and elicited functional IFNγ-producing splenocytes which recognized MU-Ag85A peptide and whole M. ulcerans better than a BCG prime-boost vaccination. Strikingly, mice vaccinated with a single subcutaneous dose of BCG MU-Ag85A or prime-boost displayed significantly enhanced survival, reduced tissue pathology, and lower bacterial load compared to mice vaccinated with BCG. Importantly, this level of superior protection against experimental Buruli ulcer compared to BCG has not previously been achieved. These results suggest that use of BCG as a recombinant vehicle expressing MU antigens represents an effective Buruli ulcer vaccine strategy and warrants further antigen discovery to improve vaccine efficacy.


Asunto(s)
Antígenos Bacterianos/inmunología , Vacunas Bacterianas/inmunología , Úlcera de Buruli/inmunología , Úlcera de Buruli/prevención & control , Mycobacterium bovis/inmunología , Mycobacterium ulcerans/inmunología , Animales , Antígenos Bacterianos/genética , Vacunas Bacterianas/administración & dosificación , Vacunas Bacterianas/genética , Linfocitos T CD4-Positivos/inmunología , Modelos Animales de Enfermedad , Femenino , Interferón gamma/metabolismo , Ratones Endogámicos C57BL , Mycobacterium bovis/genética , Mycobacterium smegmatis/genética , Mycobacterium smegmatis/inmunología , Mycobacterium ulcerans/genética , Análisis de Supervivencia , Resultado del Tratamiento , Vacunación/métodos , Vacunas Atenuadas/administración & dosificación , Vacunas Atenuadas/genética , Vacunas Atenuadas/inmunología , Vacunas Sintéticas/administración & dosificación , Vacunas Sintéticas/genética , Vacunas Sintéticas/inmunología
12.
J Clin Invest ; 125(1): 194-207, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25437876

RESUMEN

Activation of CD4+ T cells results in rapid proliferation and differentiation into effector and regulatory subsets. CD4+ effector T cell (Teff) (Th1 and Th17) and Treg subsets are metabolically distinct, yet the specific metabolic differences that modify T cell populations are uncertain. Here, we evaluated CD4+ T cell populations in murine models and determined that inflammatory Teffs maintain high expression of glycolytic genes and rely on high glycolytic rates, while Tregs are oxidative and require mitochondrial electron transport to proliferate, differentiate, and survive. Metabolic profiling revealed that pyruvate dehydrogenase (PDH) is a key bifurcation point between T cell glycolytic and oxidative metabolism. PDH function is inhibited by PDH kinases (PDHKs). PDHK1 was expressed in Th17 cells, but not Th1 cells, and at low levels in Tregs, and inhibition or knockdown of PDHK1 selectively suppressed Th17 cells and increased Tregs. This alteration in the CD4+ T cell populations was mediated in part through ROS, as N-acetyl cysteine (NAC) treatment restored Th17 cell generation. Moreover, inhibition of PDHK1 modulated immunity and protected animals against experimental autoimmune encephalomyelitis, decreasing Th17 cells and increasing Tregs. Together, these data show that CD4+ subsets utilize and require distinct metabolic programs that can be targeted to control specific T cell populations in autoimmune and inflammatory diseases.


Asunto(s)
Linfocitos T CD4-Positivos/enzimología , Encefalomielitis Autoinmune Experimental/enzimología , Proteínas Serina-Treonina Quinasas/fisiología , Animales , Diferenciación Celular , Proliferación Celular , Supervivencia Celular , Células Cultivadas , Encefalomielitis Autoinmune Experimental/inmunología , Metabolismo Energético , Glucólisis , Ratones Endogámicos C57BL , Linfocitos T Reguladores/enzimología , Células Th17/enzimología , Transcriptoma
13.
Cell Metab ; 20(1): 61-72, 2014 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-24930970

RESUMEN

CD4 T cell activation leads to proliferation and differentiation into effector (Teff) or regulatory (Treg) cells that mediate or control immunity. While each subset prefers distinct glycolytic or oxidative metabolic programs in vitro, requirements and mechanisms that control T cell glucose uptake and metabolism in vivo are uncertain. Despite expression of multiple glucose transporters, Glut1 deficiency selectively impaired metabolism and function of thymocytes and Teff. Resting T cells were normal until activated, when Glut1 deficiency prevented increased glucose uptake and glycolysis, growth, proliferation, and decreased Teff survival and differentiation. Importantly, Glut1 deficiency decreased Teff expansion and the ability to induce inflammatory disease in vivo. Treg cells, in contrast, were enriched in vivo and appeared functionally unaffected and able to suppress Teff, irrespective of Glut1 expression. These data show a selective in vivo requirement for Glut1 in metabolic reprogramming of CD4 T cell activation and Teff expansion and survival.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Transportador de Glucosa de Tipo 1/metabolismo , Animales , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/trasplante , Supervivencia Celular , Colitis/inmunología , Colitis/metabolismo , Colitis/patología , Glucosa/metabolismo , Transportador de Glucosa de Tipo 1/genética , Transportador de Glucosa de Tipo 3/genética , Transportador de Glucosa de Tipo 3/metabolismo , Glucólisis , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , ARN Mensajero/metabolismo , Linfocitos T Colaboradores-Inductores/citología , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Colaboradores-Inductores/metabolismo , Linfocitos T Reguladores/citología , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Trasplante Homólogo
14.
PLoS One ; 9(1)2014.
Artículo en Inglés | MEDLINE | ID: mdl-29220837

RESUMEN

[This corrects the article DOI: 10.1371/journal.pone.0045667.].

15.
Crit Care Med ; 41(9): e200-10, 2013 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-23478660

RESUMEN

OBJECTIVE: Cardiac surgery, especially when employing cardiopulmonary bypass and deep hypothermic circulatory arrest, is associated with systemic inflammatory responses that significantly affect morbidity and mortality. Intestinal perfusion abnormalities have been implicated in such responses, but the mechanisms linking local injury and systemic inflammation remain unclear. Intestinal mast cells are specialized immune cells that secrete various preformed effectors in response to cellular stress. We hypothesized that mast cells are activated in a microenvironment shaped by intestinal ischemia/reperfusion, and investigated local and systemic consequences. DESIGN: Rat model of deep hypothermic circulatory arrest. SETTING: University research laboratory. SUBJECTS: Twelve- to 14-week-old male Sprague-Dawley rats. INTERVENTIONS: Rats were anesthetized and cooled to 16°C to 18°C on cardiopulmonary bypass before instituting deep hypothermic circulatory arrest for 45 minutes. Specimens were harvested following rewarming and 2 hours of recovery. MEASUREMENTS AND MAIN RESULTS: Significant intestinal barrier disruption was found, together with macro- and microscopic evidence of ischemia/reperfusion injury in ileum and colon, but not in the lungs or kidneys. Immunofluorescence and toluidine blue staining revealed increased numbers of mast cells and their activation in the gut. In animals pretreated with the mast cell stabilizer, cromolyn sodium, mast cell degranulation was blocked, and intestinal morphology and barrier function were preserved following deep hypothermic circulatory arrest. Furthermore, cromolyn sodium treatment was associated with reduced intestinal neutrophil influx and blunted systemic release of proinflammatory cytokines. CONCLUSION: Our data provide primary evidence that intestinal ischemia/reperfusion is a leading pathophysiologic process in a rat model of deep hypothermic circulatory arrest, and that intestinal injury, and local and systemic inflammatory responses are critically dependent on mast cell activation. This identifies intestinal mast cells as central players in deep hypothermic circulatory arrest-associated responses, and opens novel therapeutic possibilities for patients undergoing this procedure.


Asunto(s)
Paro Circulatorio Inducido por Hipotermia Profunda , Intestinos/irrigación sanguínea , Mastocitos/fisiología , Daño por Reperfusión/prevención & control , Síndrome de Respuesta Inflamatoria Sistémica/fisiopatología , Animales , Puente Cardiopulmonar , Paro Circulatorio Inducido por Hipotermia Profunda/efectos adversos , Modelos Animales de Enfermedad , Hipotermia Inducida , Masculino , Mastocitos/inmunología , Ratas , Ratas Sprague-Dawley , Síndrome de Respuesta Inflamatoria Sistémica/etiología
16.
PLoS One ; 7(9): e45667, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-23029172

RESUMEN

The incidence and severity of allergic asthma have increased over the last century, particularly in the United States and other developed countries. This time frame was characterized by marked environmental changes, including enhanced hygiene, decreased pathogen exposure, increased exposure to inhaled pollutants, and changes in diet. Although iron is well-known to participate in critical biologic processes such as oxygen transport, energy generation, and host defense, iron deficiency remains common in the United States and world-wide. The purpose of these studies was to determine how dietary iron supplementation affected the severity of allergic inflammation in the lungs, using a classic model of IgE-mediated allergy in mice. Results showed that mice fed an iron-supplemented diet had markedly decreased allergen-induced airway hyperreactivity, eosinophil infiltration, and production of pro-inflammatory cytokines, compared with control mice on an unsupplemented diet that generated mild iron deficiency but not anemia. In vitro, iron supplementation decreased mast cell granule content, IgE-triggered degranulation, and production of pro-inflammatory cytokines post-degranulation. Taken together, these studies show that iron supplementation can decrease the severity of allergic inflammation in the lung, potentially via multiple mechanisms that affect mast cell activity. Further studies are indicated to determine the potential of iron supplementation to modulate the clinical severity of allergic diseases in humans.


Asunto(s)
Hipersensibilidad/prevención & control , Hierro/administración & dosificación , Neumonía/prevención & control , Animales , Femenino , Masculino , Mastocitos/inmunología , Ratones , Ratones Endogámicos C57BL
17.
J Am Assoc Lab Anim Sci ; 51(4): 448-57, 2012 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-23043810

RESUMEN

Immunization with complete Freund adjuvant (CFA) or incomplete Freund adjuvant (IFA) is commonly viewed as painful, yet rodents may not receive analgesics due to concerns that these drugs affect the desired immune responses. Here we tested the hypothesis that pain associated with immunization with CFA or IFA in mice can be relieved without compromising the effectiveness of the immune response. After subcutaneous immunization in the leg with antigen in CFA or IFA, mice were assessed for signs of pain by using behavioral tests, including unrestricted locomotion in an open field, forced running on an automated treadmill, and voluntary wheel running. Effects of the analgesics acetaminophen, meloxicam, and buprenorphine on behavioral and antibody responses were assessed after primary and secondary immunization with the model antigen ovalbumin and after repeated immunization with a limiting dose of recombinant protective antigen from Bacillus anthracis. Open field activity and the distance traveled during forced gait analysis and voluntary wheel running both decreased after immunization. Treatment with each of the analgesics normalized some but not all of these behaviors but did not decrease the mean or maximal antibody titer after primary or repeated immunization with a moderate dose of ovalbumin or after repeated immunization with a limiting dose of protective antigen. In summary, after immunization with CFA or IFA, mice showed behavioral responses suggestive of pain. Acetaminophen, meloxicam, and buprenorphine attenuated these effects without decreasing antibody responses. Therefore, the use of these analgesics for managing rodent pain associated with CFA- or IFA-containing vaccines can be encouraged.


Asunto(s)
Animales de Laboratorio , Adyuvante de Freund/inmunología , Inmunización/veterinaria , Ratones , Manejo del Dolor/veterinaria , Dolor/veterinaria , Acetaminofén/farmacología , Analgesia/veterinaria , Analgésicos/farmacología , Animales , Formación de Anticuerpos/efectos de los fármacos , Conducta Animal/efectos de los fármacos , Buprenorfina/farmacología , Inmunización/efectos adversos , Lípidos/inmunología , Meloxicam , Dolor/etiología , Tiazinas/farmacología , Tiazoles/farmacología
18.
PLoS One ; 7(7): e41797, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22848611

RESUMEN

Mutations that increase susceptibility to inflammatory bowel disease (IBD) have been identified in a number of genes in both humans and mice, but the factors that govern how these mutations contribute to IBD pathogenesis and result in phenotypic presentation as ulcerative colitis (UC) or Crohn disease (CD) are not well understood. In this study, mice deficient in both TNF and IL-10 (T/I mice) were found to spontaneously develop severe colitis soon after weaning, without the need for exogenous triggers. Colitis in T/I mice had clinical and histologic features similar to human UC, including a markedly increased risk of developing inflammation-associated colon cancer. Importantly, development of spontaneous colitis in these mice was prevented by antibiotic treatment. Consistent with the known role of Th17-driven inflammation in response to bacteria, T/I mice had elevated serumTh17-type cytokines when they developed spontaneous colitis and after systemic bacterial challenge via NSAID-induced degradation of the mucosal barrier. Although TNF production has been widely considered to be be pathogenic in IBD, these data indicate that the ability to produce normal levels of TNF actually protects against the spontaneous development of colitis in response to intestinal colonization by bacteria. The T/I mouse model will be useful for developing new rationally-based therapies to prevent and/or treat IBD and inflammation-associated colon cancer and may further provide important insights into the pathogenesis of UC in humans.


Asunto(s)
Colitis Ulcerosa/metabolismo , Neoplasias del Colon/metabolismo , Modelos Animales de Enfermedad , Animales , Antibacterianos/farmacología , Antiinflamatorios no Esteroideos/efectos adversos , Cruzamiento , Colitis Ulcerosa/microbiología , Colitis Ulcerosa/patología , Colitis Ulcerosa/prevención & control , Neoplasias del Colon/complicaciones , Neoplasias del Colon/patología , Neoplasias del Colon/prevención & control , Susceptibilidad a Enfermedades , Enterobacteriaceae/efectos de los fármacos , Enterobacteriaceae/fisiología , Femenino , Humanos , Inflamación/complicaciones , Interleucina-10/deficiencia , Masculino , Ratones , Ratones Endogámicos C57BL , Factor de Necrosis Tumoral alfa/deficiencia
19.
PLoS One ; 6(8): e23669, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-21858200

RESUMEN

Many commonly used non-steroidal anti-inflammatory drugs (NSAIDs) also cause gastrointestinal toxicity, including the development of life-threatening peptic ulcers. We report that mast cell-deficient mice have an extremely high incidence of severe peptic ulceration when exposed to the NSAID piroxicam. This enhanced ulcer susceptibility can be reversed by reconstitution with mast cells. Furthermore, wild type mice treated with diphenhydramine hydrochloride, a commonly used antihistamine that blocks histamine H1 receptors, develop a similarly high incidence of peptic ulcers following piroxicam exposure. The protective effect of mast cells is independent of TNF, blockade of H2 receptors, or acid secretion. These data indicate a critical role for mast cells and the histamine that they produce in prevention and/or repair of piroxicam-induced gastric mucosal injury. Additional studies will be required to determine whether this represents a NSAID class effect that can be exploited to develop novel therapeutic strategies to limit the incidence of NSAID-induced side effects in humans.


Asunto(s)
Antiinflamatorios no Esteroideos/toxicidad , Mastocitos/fisiología , Úlcera Péptica/fisiopatología , Piroxicam/toxicidad , Animales , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ciclooxigenasa 1/metabolismo , Ciclooxigenasa 2/metabolismo , Inhibidores de la Ciclooxigenasa/toxicidad , Difenhidramina/toxicidad , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patología , Mucosa Gástrica/fisiopatología , Histamina/metabolismo , Humanos , Mastocitos/metabolismo , Ratones , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Úlcera Péptica/inducido químicamente , Úlcera Péptica/genética , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo
20.
PLoS One ; 5(8): e12220, 2010 Aug 17.
Artículo en Inglés | MEDLINE | ID: mdl-20808919

RESUMEN

BACKGROUND: Inflammatory bowel disease (IBD) is hypothesized to result from stimulation of immune responses against resident intestinal bacteria within a genetically susceptible host. Mast cells may play a critical role in IBD pathogenesis, since they are typically located just beneath the intestinal mucosal barrier and can be activated by bacterial antigens. METHODOLOGY/PRINCIPAL FINDINGS: This study investigated effects of mast cells on inflammation and associated neoplasia in IBD-susceptible interleukin (IL)-10-deficient mice with and without mast cells. IL-10-deficient mast cells produced more pro-inflammatory cytokines in vitro both constitutively and when triggered, compared with wild type mast cells. However despite this enhanced in vitro response, mast cell-sufficient Il10(-/-) mice actually had decreased cecal expression of tumor necrosis factor (TNF) and interferon (IFN)-gamma mRNA, suggesting that mast cells regulate inflammation in vivo. Mast cell deficiency predisposed Il10(-/-) mice to the development of spontaneous colitis and resulted in increased intestinal permeability in vivo that preceded the development of colon inflammation. However, mast cell deficiency did not affect the severity of IBD triggered by non-steroidal anti-inflammatory agents (NSAID) exposure or helicobacter infection that also affect intestinal permeability. CONCLUSIONS/SIGNIFICANCE: Mast cells thus appear to have a primarily protective role within the colonic microenvironment by enhancing the efficacy of the mucosal barrier. In addition, although mast cells were previously implicated in progression of sporadic colon cancers, mast cells did not affect the incidence or severity of colonic neoplasia in this inflammation-associated model.


Asunto(s)
Neoplasias Colorrectales/complicaciones , Neoplasias Colorrectales/inmunología , Enfermedades Inflamatorias del Intestino/inmunología , Interleucina-10/deficiencia , Mastocitos/inmunología , Animales , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/microbiología , Susceptibilidad a Enfermedades , Helicobacter/fisiología , Humanos , Inflamación/complicaciones , Mediadores de Inflamación/metabolismo , Enfermedades Inflamatorias del Intestino/inducido químicamente , Enfermedades Inflamatorias del Intestino/metabolismo , Mucosa Intestinal/inmunología , Mucosa Intestinal/microbiología , Ratones , Piroxicam/farmacología
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