RESUMEN
Cognate interaction of chemokine receptor CCR7 on lymphocytes with its ligands CCL19 and CCL21 expressed on high endothelial venules (HEVs) is essential for effective migration of T and B cells across HEVs into secondary lymphoid organs. Plt mice, which lack expression of CCL19 and CCL21-ser, both ligands for CCR7 on HEVs, as well as CCR7-deficient mice, have a defective cell migration and reduced homing of lymphocytes. FTY720, a novel immunosuppressant, causes a reduction of lymphocytes in peripheral blood and tissues and their sequestration into lymphoid tissues. In this study we demonstrate that FTY720 rescues the homing defect in both CCR7(-/-) mice and plt mice. After FTY720 treatment, the number of CD4(+) and CD8(+) T cells as well as B cells in peripheral blood is reduced while pertussis toxin-sensitive homing into peripheral lymph nodes, mesenteric lymph node, and Peyer's patches is increased. Immunohistology demonstrates that FTY720 enables these cells to enter lymphoid tissue through HEVs. Thus, our data suggest an alternative G-alpha(i)-dependent, CCR7-CCL19/CCL21-independent mechanism for lymphocyte homing through HEVs which is strongly augmented in the presence of FTY720.
Asunto(s)
Linfocitos B/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Movimiento Celular/inmunología , Receptores de Quimiocina/inmunología , Animales , Linfocitos B/citología , Linfocitos T CD4-Positivos/citología , Linfocitos T CD8-positivos/citología , Movimiento Celular/efectos de los fármacos , Quimiocina CCL19 , Quimiocina CCL21 , Quimiocinas CC/inmunología , Clorhidrato de Fingolimod , Inmunosupresores/inmunología , Inmunosupresores/farmacología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Glicoles de Propileno/inmunología , Glicoles de Propileno/farmacología , Receptores CCR7 , Esfingosina/análogos & derivadosRESUMEN
BACKGROUND: Most people agree that dependence to tobacco is mediated by the effects of nicotine on the central nervous system, albeit the neural pathways involved are not clearly delineated. We investigated the effect of nasal nicotine spray on regional cerebral blood flow (rCBF) in a sample of habitual smokers, with H2 15O and positron emission tomography (PET). METHODS: Eighteen volunteer smokers were studied after 12 hours of smoking deprivation. Regional cerebral blood flow measures were obtained with PET and 50 mCi H2 15O in six consecutive scans. Nicotine spray and a placebo spray were administered in a single-blind design, preceded and followed by baseline studies. Images were coregistered and anatomically standardized. Square (9-mm side) regions of interest were placed in 10 preselected brain regions, bilaterally. The effects of the experimental condition and gender were tested with two-way repeated-measures analysis of variance in each of the regions studied. RESULTS: Nicotine reduced rCBF in the left anterior temporal cortex and in the right amygdala. Increases were noted in the right anterior thalamus. CONCLUSIONS: In habitual smokers after overnight abstinence, nicotine induced differing effects on regional blood flow relative to whole brain blood flow. Increases were observed in the thalamus, a region rich in nicotinic receptors, and reductions in limbic and paralimbic (amygdala, anterior temporal cortex) regions.
Asunto(s)
Encéfalo/irrigación sanguínea , Encéfalo/efectos de los fármacos , Ritmo Circadiano , Nicotina/efectos adversos , Fumar , Adolescente , Adulto , Circulación Cerebrovascular/efectos de los fármacos , Cotinina/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Nicotina/sangre , Síndrome de Abstinencia a Sustancias/etiología , Lóbulo Temporal/irrigación sanguínea , Lóbulo Temporal/efectos de los fármacos , Tálamo/irrigación sanguínea , Tálamo/efectos de los fármacos , Tomografía Computarizada de EmisiónRESUMEN
Chemokines and their receptors have been identified as major regulators controlling the functional organization of secondary lymphoid organs. Here we show that expression of CXC chemokine receptor 5 (CXCR5), a chemokine receptor required for B cell homing to B cell follicles, defines a novel subpopulation of B helper T cells localizing to follicles. In peripheral blood these cells coexpress CD45RO and the T cell homing CC chemokine receptor 7 (CCR7). In secondary lymphoid organs, CD4(+)CXCR5(+) cells lose expression of CCR7, which allows them to localize to B cell follicles and germinal centers where they express high levels of CD40 ligand (CD40L), a costimulatory molecule required for B cell activation and inducible costimulator (ICOS), a recently identified costimulatory molecule of the CD28 family. Thus, when compared with CD4(+)CD45RO(+)CXCR5(-) cells, CD4(+)CD45RO(+)CXCR5(+) tonsillar T cells efficiently support the production of immunoglobulin (Ig)A and IgG. In contrast, analysis of the memory response revealed that long-lasting memory cells are found within the CD4(+)CD45RO(+)CXCR5(-) population, suggesting that CXCR5(+)CD4 cells represent recently activated effector cells. Based on the characteristic localization within secondary lymphoid organs, we suggest to term these cells "follicular B helper T cells" (T(FH)).
Asunto(s)
Formación de Anticuerpos , Linfocitos B/inmunología , Tejido Linfoide/inmunología , Receptores de Quimiocina/biosíntesis , Receptores de Citocinas/biosíntesis , Receptores Mensajeros de Linfocitos/biosíntesis , Linfocitos T Colaboradores-Inductores/metabolismo , Antígenos de Diferenciación de Linfocitos T/biosíntesis , Antígenos de Diferenciación de Linfocitos T/genética , Linfocitos T CD4-Positivos/clasificación , Linfocitos T CD4-Positivos/inmunología , Ligando de CD40/biosíntesis , Fraccionamiento Celular , Citocinas/biosíntesis , Centro Germinal/citología , Centro Germinal/inmunología , Humanos , Inmunoglobulina A/biosíntesis , Inmunoglobulina G/biosíntesis , Inmunoglobulina M/biosíntesis , Memoria Inmunológica/inmunología , Proteína Coestimuladora de Linfocitos T Inducibles , Leucocitos Mononucleares/clasificación , Leucocitos Mononucleares/inmunología , Tejido Linfoide/citología , Receptores CCR7 , Receptores CXCR5 , Receptores de Quimiocina/genética , Receptores de Quimiocina/inmunología , Receptores de Citocinas/genética , Receptores de Citocinas/inmunología , Receptores Mensajeros de Linfocitos/genética , Receptores Mensajeros de Linfocitos/inmunología , Linfocitos T Colaboradores-Inductores/clasificación , Linfocitos T Colaboradores-Inductores/inmunologíaRESUMEN
Eleven healthy tobacco smoking adult male volunteers of mixed race were tobacco abstinent overnight for this study. In each subject, positron emission tomographic images of regional cerebral metabolism of glucose with [18F]fluorodeoxyglucose were obtained in two conditions in the morning on different days: about 3min after approximately 1-2mg of nasal nicotine spray and after an equivalent volume of an active placebo spray of oleoresin of pepper in a random counterbalanced design. A Siemens/CTI 931/08-12 scanner with the capability of 15 horizontal brain slices was used. The images were further converted into a standard uniform brain format in which the mean data of all 11 subjects were obtained. Images were analysed in stereotactic coordinates using pixel-wise t statistics and a smoothed Gaussian model. Peak plasma nicotine levels varied three-fold and the areas under the curve(0-30min) varied seven-fold among the individual subjects. Nicotine caused a small overall reduction in global cerebral metabolism of glucose but, when the data were normalized, several brain regions showed relative increases in activity. Cerebral structures specifically activated by nicotine (nicotine minus pepper, Z score >4.0) included: left inferior frontal gyrus, left posterior cingulate gyrus and right thalamus. The visual cortex, including the right and left cuneus and left lateral occipito-temporal gyrus fusiformis, also showed an increase in regional cerebral metabolism of glucose with Z scores >3. 6. Structures with a decrease in regional cerebral metabolism of glucose (pepper minus nicotine) were the left insula and right inferior occipital gyrus, with Z scores >3.5. Especially important is the fact that the thalamus is activated by nicotine. This is consistent with the high density of nicotinic cholinoceptors in that brain region. However, not all brain regions affected by nicotine are known to have many nicotinic cholinoceptors. The results are discussed in relation to the cognitive effects of nicotine.
Asunto(s)
Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Glucosa/metabolismo , Nicotina/administración & dosificación , Tabaquismo/metabolismo , Administración Intranasal , Adulto , Fenómenos Fisiológicos Cardiovasculares/efectos de los fármacos , Corteza Cerebral/anatomía & histología , Método Doble Ciego , Humanos , Masculino , Persona de Mediana Edad , Nicotina/efectos adversos , Nicotina/sangre , Descanso/fisiología , Tabaquismo/patología , Tabaquismo/fisiopatología , Tomografía Computarizada de Emisión , Vigilia/efectos de los fármacos , Vigilia/fisiologíaRESUMEN
The hypothesis for this research was that regional cerebral blood flow (rCBF) would increase following nasal nicotine administration to overnight abstinent tobacco smokers in relationship to the known brain distribution of nicotinic cholinergic receptors (nAChRs). Nine male and nine female healthy adult smokers were studied. They abstained overnight from tobacco products for 10 or more hours prior to study the next morning. Nicotine nasal spray was given in doses of 1-2.5 mg total with half in each nostril while the subject was awake and resting in a supine position. Oleoresin of pepper solution in a similar volume was used as an active placebo to control for the irritating effects of nicotine. Both substances were given single blind to the subjects. Positron emission tomography (PET) with H(2)(15)O was used to measure rCBF. The data from each subject volunteer were normalized to global activity to better assess regional brain changes. Both nasal nicotine and pepper spray produced similar increases in CBF in somesthetic area II, consistent with the irritant effects of both substances. The mean rCBF effects of nasal pepper were subtracted from those of nasal nicotine to determine the actions of nicotine alone. The latter produced increases in rCBF in the thalamus, pons, Brodman area 17 of the visual cortex, and cerebellum. Some brain areas that contain a large number of nAChRs, such as the thalamus, showed an increase in CBF. Other areas that have few nAChRs, such as the cerebellum, also showed an increase in relative CBF. The hippocampal/parahippocampal areas showed greater regional decreases (left) and lesser increases (right) in CBF that correlated with the increase in plasma arterial nicotine concentrations. The results obtained indicate complex primary and secondary effects of nicotine in which only some regional brain CBF changes correlate with the known distribution of nAChR. No gender differences were noted.
Asunto(s)
Circulación Cerebrovascular/efectos de los fármacos , Nicotina/farmacología , Agonistas Nicotínicos/farmacología , Fumar , Administración Intranasal , Adolescente , Adulto , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Capsaicina/farmacología , Circulación Cerebrovascular/fisiología , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Frecuencia Cardíaca/fisiología , Humanos , Masculino , Persona de Mediana Edad , Nicotina/sangre , Agonistas Nicotínicos/sangre , Flujo Sanguíneo Regional/efectos de los fármacos , Flujo Sanguíneo Regional/fisiología , Descanso/fisiología , Método Simple Ciego , Fumar/sangre , Tomografía Computarizada de EmisiónRESUMEN
OBJECTIVE: It has been hypothesized that anomalies in monoaminergic function underlie some of the manifestations of bipolar disorder. In this study the authors examined the possibility that trait-related abnormalities in the concentration of monoaminergic synaptic terminals may be present in patients with asymptomatic bipolar disorder type I. METHOD: The concentration of a stable presynaptic marker, the vesicular monoamine transporter protein (VMAT2), was quantified with (+)[(11)C]dihydrotetrabenazine (DTBZ) and positron emission tomography. Sixteen asymptomatic patients with bipolar I disorder who had a prior history of mania with psychosis (nine men and seven women) and individually matched healthy subjects were studied. Correlational analyses were conducted to examine the relationship between regional VMAT2 binding, cognitive function, and clinical variables. RESULTS: VMAT2 binding in the thalamus and ventral brainstem of the bipolar patients was higher than that in the comparison subjects. VMAT2 concentrations in these regions correlated with performance on measures of frontal, executive function. In addition, sex differences in VMAT2 binding were detected in the thalamus of the bipolar patients; the male patients had higher binding than the women. No sex differences in binding were observed in the healthy comparison group. CONCLUSIONS: These initial results suggest that higher than normal VMAT2 expression and, by extension, concentration of monoaminergic synaptic terminals, may represent a trait-related abnormality in patients with bipolar I disorder and that male and female patients show different patterns. Also, VMAT2 concentrations may be associated with some of the cognitive deficits encountered in euthymic bipolar disorder.
Asunto(s)
Trastorno Bipolar/metabolismo , Glicoproteínas de Membrana/metabolismo , Proteínas de Transporte de Membrana , Neuropéptidos , Tetrabenazina/análogos & derivados , Adulto , Biomarcadores , Trastorno Bipolar/diagnóstico , Trastorno Bipolar/diagnóstico por imagen , Tronco Encefálico/química , Trastornos del Conocimiento/diagnóstico , Trastornos del Conocimiento/metabolismo , Femenino , Humanos , Masculino , Glicoproteínas de Membrana/análisis , Terminales Presinápticos/química , Terminales Presinápticos/metabolismo , Factores Sexuales , Tálamo/química , Tomografía Computarizada de Emisión , Proteínas de Transporte Vesicular de Aminas Biógenas , Proteínas de Transporte Vesicular de MonoaminasRESUMEN
BACKGROUND AND OBJECTIVES: Arterial (A) and venous (V) plasma nicotine and cotinine concentrations were measured after nasal nicotine spray in tobacco smokers of both genders. The hypothesis for this research was that a greater A/V difference in plasma nicotine would be present in males than females because males have greater skeletal muscle mass to bind nicotine. SUBJECTS AND METHODS: Nine male and nine female healthy adult smokers were studied. They all abstained from use of tobacco overnight for 10 h or more prior to the study. Nicotine nasal spray was given in doses of 1-2.5 mg total, with half in each nostril while the subject was supine. Both A and V blood samples were obtained prior to and 3, 6, 10, 15, 20, and 30 min post-nasal nicotine spray. RESULTS AND CONCLUSIONS: Nasal nicotine administration produced greater A than V plasma levels. There were no gender differences in A/V nicotine concentrations, disproving the above hypothesis, suggesting that other physiochemical factors besides skeletal muscle mass must be involved. Heart rate increases correlated well with arterial plasma nicotine levels (r = 0.77). Males had less variance than females in the expected increase in arterial plasma nicotine concentrations with increased number of nasal sprays. Although there was considerable overlap, mean A cotinine concentrations were consistently slightly larger than V concentrations.