RESUMEN
Chronic lymphocytic leukemia (CLL)-B-cells are quiescent differentiated cells that produce interleukin (IL)-10 and accumulate due to resistance to apoptosis. The mechanisms underlying such resistance are poorly understood. Herein we show that all CLL B-cells tested (30/30) display high mRNA and protein expression of the tumor suppressor Mda-7/IL-24, an IL-10 family member, in comparison to normal B cells. A downstream Mda-7 signaling target, p38 mitogen-activated protein kinase (MAPK) was highly phosphorylated in all CLL cells but not in normal B-cells. Mda-7 expression and p38 MAPK phosphorylation diminished in culture and the latter could be reinduced by recombinant (r)-IL-24 or LPS and Mda-7 transfection. Mda-7/IL-24 siRNA specifically inhibited p38 MAPK phosphorylation in CLL without affecting p38 MAPK, bcl2, or Lyn expression, further demonstrating the direct role of Mda-7/IL-24 in p38 MAPK activation. Both pharmacological inhibition of p38 MAPK and Mda-7 silencing augmented spontaneous apoptosis by three-fold in CLL cells cultured in autologous serum, which was reversed by LPS and r-IL-24. We established the role of p38 MAPK in CLL cell survival and demonstrated a paradoxical effect, whereby Mda-7 and IL-24, inducers of apoptosis in diverse cancer cells, promote the survival of CLL B-cells through p38 MAPK activation.
Asunto(s)
Supervivencia Celular/genética , Interleucinas/metabolismo , Leucemia Linfocítica Crónica de Células B/enzimología , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Anciano , Anciano de 80 o más Años , Secuencia de Bases , Supervivencia Celular/efectos de los fármacos , Cartilla de ADN , Activación Enzimática , Ensayo de Inmunoadsorción Enzimática , Femenino , Glicosilación , Humanos , Interleucinas/genética , Interleucinas/farmacología , Masculino , Persona de Mediana Edad , Fosforilación , Interferencia de ARN , ARN Mensajero/genética , Proteínas Recombinantes/farmacología , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Intra-vascular lymphoma is usually reported as a rare and fatal disorder. We describe here the first case of an intra-vascular lymphoma revealed by a nephrotic syndrome for which a durable remission has been obtained by 8 cycles of bi-mensual CHOP and Rituximab therapy. In this report, 18 fluorodesoxyglucose tomoscintigraphy is discussed as a tool for intra-vascular lymphoma extension and follow-up.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ciclofosfamida/uso terapéutico , Doxorrubicina/uso terapéutico , Linfoma de Células B/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Síndrome Nefrótico/patología , Prednisona/uso terapéutico , Neoplasias Vasculares/tratamiento farmacológico , Vincristina/uso terapéutico , Anciano , Anticuerpos Monoclonales de Origen Murino , Femenino , Humanos , Linfoma de Células B/patología , Linfoma de Células B Grandes Difuso/patología , Inducción de Remisión , Rituximab , Tomografía Computarizada de Emisión de Fotón Único , Neoplasias Vasculares/patologíaRESUMEN
Dendritic-cell (DC) trafficking and function in tumors is poorly characterized, with studies confined to myeloid DCs (DC1s). Tumors inhibit DC1 migration and function, likely hindering specific immunity. The role of plasmacytoid DCs (DC2s) in tumor immunity is unknown. We show here that malignant human ovarian epithelial tumor cells express very high levels of stromal-derived factor-1, which induces DC2 precursor (preDC2) chemotaxis and adhesion/transmigration, upregulates preDC2 very late antigen (VLA)-5, and protects preDC2s from tumor macrophage interleukin-10-induced apoptosis, all through CXC chemokine receptor-4. The VLA-5 ligand vascular-cell adhesion molecule-1 mediated preDC2 adhesion/transmigration. Tumor preDC2s induced significant T-cell interleukin-10 unrelated to preDC2 differentiation or activation state, and this contributed to poor T-cell activation. Myeloid precursor DCs (preDC1s) were not detected. Tumors may weaken immunity by attracting preDC2s and protecting them from the harsh microenvironment, and by altering preDC1 distribution.
Asunto(s)
Carcinoma/inmunología , Quimiocinas CXC/farmacología , Células Dendríticas/efectos de los fármacos , Neoplasias Ováricas/inmunología , Células Madre/efectos de los fármacos , Apoptosis , Carcinoma/irrigación sanguínea , Quimiocina CXCL12 , Quimiotaxis de Leucocito , Células Dendríticas/citología , Femenino , Humanos , Interleucina-10/farmacología , Activación de Linfocitos , Neoplasias Ováricas/irrigación sanguínea , Receptores de Fibronectina/biosíntesis , Células Madre/citología , Linfocitos T/inmunología , Molécula 1 de Adhesión Celular Vascular/biosíntesisRESUMEN
Disseminated candidiasis, especially ocular infections such as endophthalmitis, is uncommon in HIV-infected patients. We report a case of candidal endophthalmitis in an HIV-positive non-drug-user patient, following candidemia from a cutaneous abscess at the site of a peripheral catheter. Ocular disease was revealed by a visual decrease in the left eye. DNA analysis using RAPD showed identical patterns of Candida albicans isolated from the skin and eye. Combination therapy with high-dose fluconazole and intravenous amphotericin B was performed. Two intravitreal amphotericin B injections and a vitrectomy were administered because of an amblyopic right eye and severe vitritis. The outcome was favorable without relapse at 18 months.
Asunto(s)
Infecciones Oportunistas Relacionadas con el SIDA/diagnóstico , Candida albicans/aislamiento & purificación , Candidiasis/diagnóstico , Endoftalmitis/diagnóstico , Trastornos de la Visión/microbiología , Adulto , Candida albicans/genética , Candidiasis/microbiología , Endoftalmitis/microbiología , Humanos , MasculinoRESUMEN
Strains of human immunodeficiency virus (HIV) transmitted between individuals use the CCR5 coreceptor, but no preferential depletion of particular Th-lymphocyte subpopulations has been reported during primary HIV infection (PHI). In contrast, gut-associated Th lymphocytes are preferentially depleted in macaques recently infected by simian immunodeficiency virus. The expression of CCR5 and the intestinal homing receptor integrin alpha4beta7 on subpopulations of Th lymphocytes was studied in 12 patients with PHI. There was a profound decrease of circulating alpha4beta7+ Th lymphocytes and CCR5+ memory Th lymphocytes with nonlymphoid homing potential (CD62L-CD45RO+). Unlike other Th lymphocytes, this cell population remained depleted despite early control of viral replication under antiretroviral treatment. Therefore, HIV preferentially targets a specific CCR5+ subpopulation of Th lymphocytes early during infection, inducing its persistent depletion despite treatment. Protective immunity in vivo depends on Th lymphocytes carrying homing capacity to nonlymphoid tissue, and therefore these data may explain the persistent abnormalities of immune functions in patients infected with HIV.
Asunto(s)
Terapia Antirretroviral Altamente Activa , Recuento de Linfocito CD4 , Infecciones por VIH/patología , Integrinas/análisis , Receptores CCR5/análisis , Receptores Mensajeros de Linfocitos/análisis , Subgrupos de Linfocitos T/patología , Linfocitos T Colaboradores-Inductores/patología , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , VIH-1/efectos de los fármacos , VIH-1/fisiología , Humanos , Intestinos/inmunología , Selectina L/análisis , Antígenos Comunes de Leucocito/análisis , Especificidad de Órganos , Subgrupos de Linfocitos T/química , Subgrupos de Linfocitos T/virología , Linfocitos T Colaboradores-Inductores/química , Linfocitos T Colaboradores-Inductores/virología , Replicación Viral/efectos de los fármacosRESUMEN
Glioma and renal cell carcinoma (RCC) cells express high affinity interleukin 13 (IL13) binding sites, but only RCC cell proliferation was inhibited by IL13. Both of these two cell types are IL2-receptor (gamma)c chain-negative. We thus used these cell models to investigate the patterns of expression of IL13Ralpha1, IL13Ralpha2, and IL4Ralpha chains and the role of IL13Ralpha2 in the response to IL13. Using new specific antibodies and flow cytometry, we observed a similar surface expression of IL4Ralpha and IL13Ralpha1 chains in most RCC and glioma cells, whereas IL13Ralpha2 was only present on five of six glioma cell lines. In all glioma cell lines, the amount of IL13Ralpha2 expression was 10 to 30 times higher than that of the two other chains. Although there was no surface or intracellular expression of IL13Ralpha2, its mRNA was detected in three of seven RCC cell lines. The expression on RCC cells of IL13Ralpha2 mRNA and/or that of high-affinity IL13 binding sites is not sufficient to predict IL13Ralpha2 protein expression. Blocking experiments showed that IL4 and IL13 strongly inhibited RCC cell proliferation through a unique receptor composed of IL4Ralpha and IL13Ralpha1 chains. Using RCC cells stably transfected with IL13Ralpha2 cDNA, we showed that the overexpression of IL13Ralpha2 decreased the response to IL13 but not that to IL4. Our results demonstrate that IL13Ralpha2 acts as a decoy receptor for IL13 and that it may exert a tight regulation of IL13 activity without impairing the IL4 response of the same cell target.
Asunto(s)
Carcinoma de Células Renales/metabolismo , Neoplasias del Sistema Nervioso Central/metabolismo , Glioma/metabolismo , Neoplasias Renales/metabolismo , Receptores de Interleucina/metabolismo , Membrana Celular/metabolismo , Interleucina-13/farmacología , Interleucina-4/farmacología , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , ARN Mensajero/metabolismo , Receptores de Interleucina/genética , Receptores de Interleucina/fisiología , Receptores de Interleucina-13 , Receptores de Interleucina-4/genética , Receptores de Interleucina-4/metabolismo , Receptores de Interleucina-4/fisiología , Extractos de Tejidos/metabolismo , Células Tumorales Cultivadas/efectos de los fármacosRESUMEN
Fractalkine is the only member of the CX3C chemokine family. Polymorphism of the fractalkine receptor gene may influence the prognosis of human immunodeficiency virus (HIV) infection, but the nature of the cells expressing fractalkine or its receptor in HIV-infected patients remains unknown. We show that, in contrast to HIV-uninfected individuals, a large number of cells expressed fractalkine in T-cell zones of lymph nodes from HIV-infected patients. CD83(+) mature and CD123(+) plasmacytoid dendritic cells as well as plasma cells are involved in this increased expression of fractalkine. Increased numbers of plasmacytoid dendritic cells and plasma cells were present in T-cell zones of HIV-infected patients. CD83(+) dendritic cells were present in similar number in HIV-infected patients and controls, but an increased fraction of these cells produced fractalkine in HIV-infected patients. Many plasma cells in the gut-associated lymphoid tissue from HIV-infected patients also produced fractalkine, whereas few cells produced fractalkine in the gut of controls. The fraction of CD45RO(+) and CD45RO(-) T helper (Th) cells expressing the fractalkine receptor CX3CR1 was higher in HIV-infected patients than in healthy individuals, and these cells were abnormally sensitive to fractalkine stimulation. This increased response correlated with HIV viremia, and it returned to normal levels in patients successfully treated with antiretroviral drugs. The increased expression of the fractalkine/fractalkine receptor complex associated with HIV infection may affect adhesion and migration of Th lymphocytes and their interaction with dendritic cells. Thus, it may influence the equilibrium between depletion and renewal of the Th lymphocyte compartment.
Asunto(s)
Quimiocinas CX3C/biosíntesis , Infecciones por VIH/inmunología , VIH-1 , Proteínas de la Membrana/biosíntesis , Receptores de Citocinas/metabolismo , Receptores del VIH/metabolismo , Antígenos CD , Recuento de Linfocito CD4 , Receptor 1 de Quimiocinas CX3C , Quimiocina CX3CL1 , Quimiocinas CX3C/genética , Células Dendríticas/química , Células Dendríticas/inmunología , Duodeno/inmunología , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , VIH-1/crecimiento & desarrollo , Humanos , Inmunoglobulinas/análisis , Interleucina-2/farmacología , Subunidad alfa del Receptor de Interleucina-3 , Ganglios Linfáticos/inmunología , Glicoproteínas de Membrana/análisis , Proteínas de la Membrana/genética , Células Plasmáticas/inmunología , ARN Mensajero/biosíntesis , Receptores de Citocinas/fisiología , Receptores del VIH/fisiología , Receptores de Interleucina-3/análisis , Linfocitos T Colaboradores-Inductores/inmunología , Transcripción Genética , Regulación hacia Arriba , Carga Viral , Antígeno CD83RESUMEN
The general properties of chemokines and their receptors are described, and the perspectives raised for cellular therapy are discussed. Specific examples are provided in the cases of the CXC chemokine SDF1 and of chemokines ligands of CCR5.
Asunto(s)
Movimiento Celular/fisiología , Quimiocinas/fisiología , Sistema Inmunológico/citología , Receptores de Quimiocina/fisiología , Animales , Quimiocina CCL4 , Quimiocina CCL5/fisiología , Quimiocina CXCL12 , Quimiocinas/antagonistas & inhibidores , Quimiocinas/clasificación , Quimiocinas CXC/fisiología , Quimiotaxis de Leucocito/fisiología , Células Madre Hematopoyéticas/citología , Humanos , Inflamación/metabolismo , Subgrupos Linfocitarios/citología , Proteínas Inflamatorias de Macrófagos/fisiología , Receptores CCR5/efectos de los fármacos , Receptores CCR5/fisiología , Receptores CXCR4/efectos de los fármacos , Receptores CXCR4/fisiología , Receptores de Quimiocina/clasificación , Receptores de Quimiocina/efectos de los fármacosRESUMEN
IFN alpha has both antiviral and immunostimulating properties. The ANRS086 Primoferon A Study evaluated in 12 patients with primary HIV infection the tolerance and efficacy of an early and transient administration of pegylated IFN alpha, in addition to highly active antiretroviral therapy. Tolerance was good, and this regimen allowed the early control of HIV replication and rapid decay of the viral reservoir. These results support the initiation of comparative studies with pegylated INF alpha in primary HIV infection.
Asunto(s)
Terapia Antirretroviral Altamente Activa , Antivirales/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , VIH-1 , Interferón-alfa/uso terapéutico , Polietilenglicoles/uso terapéutico , Recuento de Linfocito CD4 , Ensayo de Inmunoadsorción Enzimática , Proteína p24 del Núcleo del VIH/inmunología , Infecciones por VIH/inmunología , Humanos , Interferón alfa-2 , ARN Viral/sangre , Proteínas Recombinantes , Replicación ViralRESUMEN
Wegener's granulomatosis (WG) is an inflammatory, destructive, angiotropic lesion. The inflammatory process involves accumulation of macrophages, lymphocytes, and polymorphonuclear neutrophils. We studied 6 lung biopsy specimens from patients with WG to characterize the cellular infiltrate and to analyze the mechanism of immune cell recruitment. We show that lymphocytes accumulating in WG lesions are mostly memory CD4(+)CD45RO(+) T lymphocytes and, although less numerous, CD8(+)CD45RO(+) T lymphocytes. Few if any B lymphocytes or natural killer cells are present within lesions. The chemokine RANTES (regulated upon activation in normal T cells, expressed and secreted) has been reported to recruit memory T lymphocytes and macrophages selectively. We used reverse-transcription polymerase chain reaction, in situ hybridization, and immunohistochemistry to study its production in WG. RANTES was expressed at a higher level in WG lungs than in normal controls, especially around microabscesses. As visualized immunohistochemically in serial sections with anti-RANTES monoclonal antibody, RANTES production was produced mainly by macrophages. Expression of the gene coding for interferon-gamma (IFN-gamma), a potent RANTES inducer, was also studied. Its expression was also much stronger in WG than in controls. Our observations are consistent with a cascade of events leading to the recruitment of immune cells in WG, sequentially involving production of IFN-gamma by T lymphocytes and RANTES production by macrophages, leading to the homing of memory T-helper lymphocytes and macrophages. HUM PATHOL 32:320-326.
Asunto(s)
Quimiocina CCL5/genética , Expresión Génica , Granulomatosis con Poliangitis/metabolismo , Enfermedades Pulmonares/metabolismo , Adulto , Anciano , Anticuerpos Monoclonales , Linfocitos B/química , Linfocitos B/patología , Biopsia , Linfocitos T CD4-Positivos/química , Linfocitos T CD4-Positivos/patología , Quimiocina CCL5/análisis , Femenino , Granulomatosis con Poliangitis/patología , Humanos , Inmunohistoquímica , Hibridación in Situ , Interferón gamma/genética , Antígenos Comunes de Leucocito/análisis , Enfermedades Pulmonares/patología , Macrófagos/química , Macrófagos/metabolismo , Macrófagos/patología , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Linfocitos T/química , Linfocitos T/patologíaRESUMEN
B1a lymphocytes accumulate and proliferate in the peritoneal cavity. Stromal cell-derived factor 1 (SDF-1) is a chemotactic and growth promoting factor for B cell precursors. It is required for fetal liver B cell lymphopoiesis, which generates mostly B1a lymphocytes. Using immunohistochemistry with an anti-SDF-1 monoclonal antibody, we found that SDF-1 was produced by peritoneal mesothelial cells in adult mice. Peritoneal B1a lymphocytes expressed a functional SDF-1 receptor, as shown by actin polymerization experiments. In vitro, SDF-1 stimulated migration, proliferation of a minority of peritoneal B1a lymphocytes, and prevented apoptosis in a large fraction of cells. B1a cells migrating in response to SDF-1 were largely enriched in the CD5(high)CD43(high)B220(-)CD1d(-) subpopulation. In vivo, neutralization of SDF-1 for 3 weeks significantly decreased the number of peritoneal B1 cells. SDF-1 also acted on peritoneal B2 cells. These findings show that after the cessation of B cell lymphopoiesis in the liver, around birth, the persistence of B1a cells remains SDF-1 dependent, and that SDF-1 production by mesothelial cells plays a role in the peritoneal location of B1a cells. Thus, the role of mesothelial cells for B1a cells in adults may be similar to that of SDF-1-producing biliary ductal plate cells in the fetus, and to that of bone marrow stromal cells for B2 cell precursors.
Asunto(s)
Linfocitos B/fisiología , Quimiocinas CXC/biosíntesis , Animales , Movimiento Celular/efectos de los fármacos , Supervivencia Celular , Quimiocina CXCL12 , Quimiocinas CXC/farmacología , Factores Quimiotácticos/farmacología , Células Epiteliales/metabolismo , Femenino , Hematopoyesis , Activación de Linfocitos/efectos de los fármacos , Ratones , Ratones Endogámicos BALB C , Receptores CXCR4/fisiologíaRESUMEN
OBJECTIVES: In experimental models, liver injury induced by ethanol, cytotoxic activity of tumor necrosis factor (TNF) -alpha is principally mediated by TNF receptor p55 (TNFRp55). Among the various mechanisms underlying the toxic effects of TNF-alpha, overproduction of reactive oxygen species seems to play a key role in mediating TNF-alpha-induced cytotoxicity. The aim of this study was to evaluate, in patients with alcoholic liver disease, whether alcohol TNFRp55-mediated hepatotoxicity could account for lipid peroxidation expressed by significant increase in serum thiobarbituric reactive acid substances (TBARS) content, and could be amplified by decrease in blood total glutathione content and decrease in plasma antioxidant protective capacity. METHODS: We studied 27 patients with histological alcoholic liver disease (five fibrosis, six acute alcoholic hepatitis (AAH) without cirrhosis, four cirrhosis without AAH, and 12 cirrhosis with AAH. TNFsRp55 and TNFsRp75 plasma levels were measured using ELISA assays. Plasma lipid peroxidation was evaluated by the content of TBARS. Total glutathione (tGSH) content in blood was determined by a kinetic assay. The sensitivity of erythrocytes to an oxidative stress and the plasma antioxidant protective capacity were simultaneously determined by a simple method. RESULTS: In the 18 patients with mild or severe AAH, the plasma levels of TNFsRp55 were negatively correlated with tGSH and were positively correlated with TBARS, with total bilirubin and with discriminant function. tGSH was positively correlated with plasma selenium. The plasma levels of TNFsRp75 were positively correlated with TBARS and with total bilirubin. There was no significant correlation with the mean inhibitory 50% plasma volume or with the percentage of hemolyzed erythrocytes. CONCLUSIONS: Our data support the notions that, in patients with AAH, TNFsRp55 probably mediates cytotoxicity of TNF-alpha, and that cytotoxic effect could be amplified by tGSH depletion in enhancing lipid peroxidation.
Asunto(s)
Antígenos CD/metabolismo , Hepatitis Alcohólica/metabolismo , Peróxidos Lipídicos/metabolismo , Receptores del Factor de Necrosis Tumoral/metabolismo , Enfermedad Aguda , Antígenos CD/química , Bilirrubina/sangre , Femenino , Glutatión/sangre , Humanos , Masculino , Persona de Mediana Edad , Receptores del Factor de Necrosis Tumoral/química , Receptores Tipo I de Factores de Necrosis Tumoral , Solubilidad , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismoAsunto(s)
Anticuerpos Monoclonales/uso terapéutico , Citocinas/antagonistas & inhibidores , Citocinas/uso terapéutico , Inmunoterapia/métodos , Inhibidores de la Angiogénesis/uso terapéutico , Anticuerpos Monoclonales/inmunología , Antineoplásicos/uso terapéutico , Antivirales/uso terapéutico , Citocinas/inmunología , Humanos , Inmunoterapia/tendencias , Interferón Tipo I/uso terapéutico , Interleucina-2/uso terapéutico , Proteínas Recombinantes , Factor de Necrosis Tumoral alfa/antagonistas & inhibidoresRESUMEN
Monocyte-derived dendritic cells (MDDCs) activate naive T lymphocytes to induce adaptive immunity, effecting Th1 polarization through IL-12. However, little is known about other potential DC Th1 polarizing mechanisms, or how T cell polarization may be affected by DCs differentiating in, or exposed to, a proinflammatory environment. Macrophages (MPhis) are DC precursors abundant in inflamed tissues, lymph nodes, and tumors. Thus we studied the T cell-activating and -polarizing properties of MPhi-derived DCs (PhiDCs). Monocytes were cultured in MPhi-CSF (M-CSF) to produce MPhis, which were then differentiated into DCs following culture with GM-CSF plus IL-4. PhiDCs activated a significant allogeneic MLR and were significantly better than MDDCs in activating T cells with superantigen. Most strikingly, PhiDCs elicited up to 9-fold more IFN-gamma from naive or Ag-specific T cells compared with MDDCs (with equivalent IL-4 secretion), despite producing up to 9-fold less IL-12. Neutralization of MDDC, but not PhiDC IL-12 significantly inhibited T cell IFN-gamma induction. PhiDCs produced up to 12-fold more beta-chemokines (macrophage-inflammatory protein-1alpha, -1beta, and RANTES) than MDDCs. Ab blockade of CCR5, but not CXC chemokine receptor 4, inhibited T cell IFN-gamma induction by PhiDCs significantly greater than by MDDCs. Thus DCs differentiating from MPhis induce T cell IFN-gamma through beta-chemokines with little or no requirement for IL-12. Myeloid DCs arising from distinct precursor cells may have differing properties, including different mechanisms of Th1 polarization. These data are the first reports of IFN-gamma induction through chemokines by DCs.
Asunto(s)
Polaridad Celular/inmunología , Quimiocinas CC/fisiología , Células Dendríticas/inmunología , Interleucina-12/fisiología , Macrófagos/inmunología , Células TH1/inmunología , Antígenos CD/biosíntesis , Antígenos de Superficie/biosíntesis , Apoptosis/inmunología , Antígeno B7-1/biosíntesis , Antígeno B7-2 , Antígenos CD36/biosíntesis , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/inmunología , Diferenciación Celular/inmunología , Células Cultivadas , Quimiocinas CC/metabolismo , Células Dendríticas/citología , Células Dendríticas/metabolismo , Sinergismo Farmacológico , Enterotoxinas/inmunología , Epítopos de Linfocito T/inmunología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/farmacología , Antígenos de Histocompatibilidad Clase I/biosíntesis , Humanos , Integrinas/biosíntesis , Molécula 1 de Adhesión Intercelular/biosíntesis , Interferón gamma/biosíntesis , Interferón gamma/metabolismo , Interleucina-10/metabolismo , Interleucina-12/biosíntesis , Interleucina-12/metabolismo , Interleucina-4/farmacología , Antígenos Comunes de Leucocito/biosíntesis , Receptores de Lipopolisacáridos/biosíntesis , Lipopolisacáridos/farmacología , Activación de Linfocitos , Factor Estimulante de Colonias de Macrófagos/farmacología , Macrófagos/citología , Macrófagos/metabolismo , Glicoproteínas de Membrana/biosíntesis , Células Mieloides/inmunología , Células Mieloides/metabolismo , Receptores CCR5/fisiología , Receptores de Vitronectina/biosíntesis , Staphylococcus aureus/inmunología , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismoRESUMEN
The regulation of CCR6 (chemokine receptor 6) expression during B-cell ontogeny and antigen-driven B-cell differentiation was analyzed. None of the CD34(+)Lin(-) hematopoietic stem cell progenitors or the CD34(+)CD19(+) (pro-B) or the CD19(+)CD10(+) (pre-B/immature B cells) B-cell progenitors expressed CCR6. CCR6 is acquired when CD10 is lost and B-cell progeny matures, entering into the surface immunoglobulin D(+) (sIgD(+)) mature B-cell pool. CCR6 is expressed by all bone marrow-, umbilical cord blood-, and peripheral blood-derived naive and/or memory B cells but is absent from germinal center (GC) B cells of secondary lymphoid organs. CCR6 is down-regulated after B-cell antigen receptor triggering and remains absent during differentiation into immunoglobulin-secreting plasma cells, whereas it is reacquired at the stage of post-GC memory B cells. Thus, within the B-cell compartment, CCR6 expression is restricted to functionally mature cells capable of responding to antigen challenge. In transmigration chemotactic assays, macrophage inflammatory protein (MIP)-3alpha/CC chemokine ligand 20 (CCL20) induced vigorous migration of B cells with differential chemotactic preference toward sIgD(-) memory B cells. These data suggest that restricted patterns of CCR6 expression and MIP-3alpha/CCL20 responsiveness are integral parts of the process of B-lineage maturation and antigen-driven B-cell differentiation.
Asunto(s)
Linfocitos B/metabolismo , Quimiocinas CC , Regulación de la Expresión Génica/efectos de los fármacos , Proteínas Inflamatorias de Macrófagos/farmacología , Receptores de Quimiocina/genética , Actinas/metabolismo , Linfocitos B/ultraestructura , Diferenciación Celular , Quimiocina CCL20 , Factores Quimiotácticos/farmacología , Quimiotaxis de Leucocito , Citocinas/farmacología , Citoesqueleto/metabolismo , Humanos , Tejido Linfoide/citología , Mieloma Múltiple , Células Plasmáticas/citología , Receptores de Antígenos de Linfocitos B/fisiología , Receptores CCR6 , Células Tumorales CultivadasRESUMEN
OBJECTIVE: To evaluate the safety and clinical efficacy of administering an anti-interleukin-10 (anti-IL-10) monoclonal antibody (mAb) to systemic lupus erythematosus (SLE) patients with active and steroid-dependent disease. In addition, we sought to assess the effects of in vivo IL-10 neutralization on biologic markers of SLE. METHODS: Treatment consisted of 20 mg/day intravenous administration of an anti-IL-10 murine mAb (B-N10) for 21 consecutive days, with a followup period of 6 months. Six patients were studied. RESULTS: Treatment was safe and well tolerated. All patients developed antibodies against B-N10. Cutaneous lesions and joint symptoms improved in all patients beginning during B-N10 administration and continuing to month 6. The SLE Disease Activity Index decreased from a mean +/- SEM of 8.83+/-0.91 on day 1 to 3.67+/-0.67 on day 21 (P = 0.001), 1.50+/-0.84 at month 2, and 1.33+/-0.80 at month 6 (P<0.001). At the end of followup, the disease was clinically inactive in 5 of the 6 patients. Prednisone administration was decreased from a mean +/- SEM of 27.9+/-5.7 mg/day on day 1 to 9.6+/-2.0 mg/day at month 6 (P<0.005). Activity of immune and endothelial cells rapidly decreased, as assessed by the early evolution of several biologic markers. CONCLUSION: This is the first report of IL-10 antagonist administration to humans. The study shows the involvement of IL-10 in the pathogenesis of SLE, and indicates that the use of IL-10 antagonists may be beneficial in the management of refractory SLE.
Asunto(s)
Interleucina-10/inmunología , Lupus Eritematoso Sistémico/tratamiento farmacológico , Adolescente , Adulto , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/sangre , Femenino , Estudios de Seguimiento , Humanos , Interleucina-10/sangre , Masculino , Proyectos PilotoAsunto(s)
Quimiocinas CXC/metabolismo , Infecciones por VIH/transmisión , Transmisión Vertical de Enfermedad Infecciosa/prevención & control , Placenta/metabolismo , Amnios/metabolismo , Quimiocina CXCL12 , Femenino , Edad Gestacional , Humanos , Inmunohistoquímica , Placenta/citología , Embarazo , Complicaciones Infecciosas del EmbarazoRESUMEN
It would be of great value to be able to predict, before the initiation of treatment, which patients with hepatitis C virus-induced chronic hepatitis will be cured by interferon-alpha (IFN-alpha). Competitive RT-PCR was used to evaluate spontaneous expression of the perforin gene, a marker of cytotoxic cell activation, by circulating mononuclear cells in 17 patients undergoing IFN-alpha treatment. IFN-alpha increased perforin gene expression (p < 0.003), but this was not correlated with outcome. In contrast, pretreatment perforin gene expression levels were higher in the 8 patients with a sustained biochemical response after treatment than in the 9 non-responsive patients (p = 0.01). This factor predicted favorable clinical outcome with a sensitivity of 75% and a specificity of 89%. Thus, pretreatment immunological status has a major influence on the ability of IFN-alpha to cure chronic hepatitis C, and the evaluation of perforin gene expression may help to select patients that will benefit from IFN-alpha treatment.
Asunto(s)
Linfocitos T CD8-positivos/metabolismo , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/genética , Interferón-alfa/uso terapéutico , Glicoproteínas de Membrana/metabolismo , Adulto , Alanina Transaminasa/sangre , Secuencia de Bases , Cartilla de ADN/genética , Femenino , Expresión Génica , Hepacivirus/efectos de los fármacos , Hepatitis C Crónica/enzimología , Humanos , Interferón alfa-2 , Masculino , Glicoproteínas de Membrana/inmunología , Persona de Mediana Edad , Perforina , Proteínas Citotóxicas Formadoras de Poros , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteínas Recombinantes , Reproducibilidad de los Resultados , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/estadística & datos numéricos , Replicación Viral/efectos de los fármacosRESUMEN
Expression and function of the fractalkine receptor CX3CR1 by T lymphocyte subpopulations was evaluated in healthy individuals. In CD8(+) T lymphocytes, CX3CR1 was expressed by and functional in both CD45RO(-) and CD45RO(+) cells. In CD4(+) T lymphocytes, CX3CR1 was expressed mainly by CD45RO(+) cells, and almost exclusively by activated HLA-DR(+) T lymphocytes. This receptor was functional in CD45RO(+) cells, but not in CD45RO(-) cells. Expression of fractalkine was detected by in situ hybridization and immunohistochemistry in endothelial cells of normal lung and thymus. In hyperplastic lymph nodes, fractalkine was expressed by endothelial cells of high endothelial venules and of subcapsular vessels, by follicular dendritic cells (FDC) and by some follicle lymphocytes. Fractalkine mRNA was constitutively present in the HK FDC-like cell line, and it was induced in vitro in B lymphocytes stimulated by an anti-micro or by a CD40 mAb. These findings indicate that fractalkine may contribute to the recruitment of effector T helper lymphocytes, either in peripheral tissues or in lymphoid organs. In these tissues, fractalkine and its receptor may favor contact within follicles between activated T helper lymphocytes, activated B lymphocytes and FDC, thus contributing to the maturation of the B lymphocyte response.