Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 7 de 7
Filtrar
Más filtros












Base de datos
Intervalo de año de publicación
1.
J Clin Invest ; 123(6): 2590-603, 2013 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-23676465

RESUMEN

TNF has remarkable antitumor activities; however, therapeutic applications have not been possible because of the systemic and lethal proinflammatory effects induced by TNF. Both the antitumor and inflammatory effects of TNF are mediated by the TNF receptor p55 (p55TNFR) (encoded by the Tnfrsf1a gene). The antitumor effect stems from an induction of cell death in tumor endothelium, but the cell type that initiates the lethal inflammatory cascade has been unclear. Using conditional Tnfrsf1a knockout or reactivation mice, we found that the expression level of p55TNFR in intestinal epithelial cells (IECs) is a crucial determinant in TNF-induced lethal inflammation. Remarkably, tumor endothelium and IECs exhibited differential sensitivities to TNF when p55TNFR levels were reduced. Tumor-bearing Tnfrsf1a⁺⁺/⁻ or IEC-specific p55TNFR-deficient mice showed resistance to TNF-induced lethality, while the tumor endothelium remained fully responsive to TNF-induced apoptosis and tumors regressed. We demonstrate proof of principle for clinical application of this approach using neutralizing anti-human p55TNFR antibodies in human TNFRSF1A knockin mice. Our results uncover an important cellular basis of TNF toxicity and reveal that IEC-specific or systemic reduction of p55TNFR mitigates TNF toxicity without loss of antitumor efficacy.


Asunto(s)
Antineoplásicos/farmacología , Mucosa Intestinal/efectos de los fármacos , Melanoma Experimental/tratamiento farmacológico , Receptores Tipo I de Factores de Necrosis Tumoral/genética , Factor de Necrosis Tumoral alfa/farmacología , Animales , Anticuerpos Monoclonales/farmacología , Antineoplásicos/uso terapéutico , Antineoplásicos/toxicidad , Apoptosis , Citocinas/genética , Citocinas/metabolismo , Ensayos de Selección de Medicamentos Antitumorales , Endotelio/patología , Expresión Génica , Técnicas de Sustitución del Gen , Humanos , Inflamación/inducido químicamente , Interferón gamma/fisiología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Melanoma Experimental/metabolismo , Melanoma Experimental/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Trasplante de Neoplasias , Receptores Tipo I de Factores de Necrosis Tumoral/antagonistas & inhibidores , Receptores Tipo I de Factores de Necrosis Tumoral/metabolismo , Transducción de Señal , Factor de Necrosis Tumoral alfa/uso terapéutico , Factor de Necrosis Tumoral alfa/toxicidad
2.
Curr Dir Autoimmun ; 11: 1-26, 2010.
Artículo en Inglés | MEDLINE | ID: mdl-20173385

RESUMEN

The TNF/TNF receptor (TNFR) system has a prominent role in the pathogenesis of chronic inflammatory and autoimmune disorders. Extensive research in animal models with deregulated TNF expression has documented that TNF may initiate or sustain inflammatory pathology, while at the same time may exert immunomodulatory or disease-suppressive activities. The TNF/TNFR system encompassing both the soluble and the transmembrane form of TNF with differential biological activities, as well as the differential usage of its receptors, mediating distinct functions, appears to confer complexity but also specificity in the action of TNF. The inherent complexity in TNF-mediated pathophysiology highlights the requirement to address the role of TNF taking into account both proinflammatory tissue-damaging and immunomodulatory functions in a cellular and receptor-specific manner. In this review, we discuss our current understanding of the involvement of TNF in chronic inflammation and autoimmunity, focusing on TNF-mediated cellular pathways leading to the pathogenesis or progression of joint and intestinal inflammatory pathology. Knowledge of the mechanisms by which TNF either initiates or contributes to disease pathology is fundamentally required for the design of safe and effective anti-TNF/TNFR therapies for human inflammatory and autoimmune disorders.


Asunto(s)
Autoinmunidad/inmunología , Inflamación/inmunología , Modelos Inmunológicos , Factor de Necrosis Tumoral alfa/inmunología , Animales , Artritis Reumatoide/etiología , Artritis Reumatoide/inmunología , Autoinmunidad/genética , Células Dendríticas Foliculares/inmunología , Modelos Animales de Enfermedad , Humanos , Inflamación/etiología , Enfermedades Inflamatorias del Intestino/etiología , Enfermedades Inflamatorias del Intestino/inmunología , Mesodermo/inmunología , Receptores del Factor de Necrosis Tumoral/inmunología , Receptores Tipo I de Factores de Necrosis Tumoral/inmunología , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/fisiología
3.
J Exp Med ; 206(5): 1167-79, 2009 May 11.
Artículo en Inglés | MEDLINE | ID: mdl-19398754

RESUMEN

Heme oxygenase-1 (HO-1) is a key cytoprotective, antioxidant, and antiinflammatory molecule. The pathophysiological functions of HO-1 have been associated with its enzymatic activities in heme catabolism. We have examined the immune functions of HO-1 by its conditional ablation in myeloid cells (HO-1(M-KO) mice). We demonstrate that myeloid HO-1 is required for the activation of interferon (IFN) regulatory factor (IRF) 3 after Toll-like receptor 3 or 4 stimulation, or viral infection. HO-1-deficient macrophages show reduced expression of IFN-beta and of primary IRF3 target genes encoding RANTES, IP-10 and MCP-1. In the presence of polyI:C, myeloid HO-1 knockout mice infected with Listeria monocytogenes, a model dependent on IFN-beta production, showed enhanced bacterial clearance and survival, whereas control mice succumbed to infection. Moreover, after induction of experimental autoimmune encephalomyelitis, mice with myeloid-specific HO-1 deficiency developed a higher incidence and an exacerbated, nonremitting clinical disease correlating with persistent activation of antigen-presenting cells, enhanced infiltration of Th17 cells, and a nonregressing myelin-specific T cell reactivity. Notably, these defects were rectified by exogenous administration of IFN-beta, confirming that HO-1 functions directly upstream of this critical immune pathway. These results uncover a novel direct function for myeloid HO-1 in the regulation of IFN-beta production, establishing HO-1 as a critical early mediator of the innate immune response.


Asunto(s)
Hemo-Oxigenasa 1/inmunología , Interferón beta/inmunología , Células Mieloides/enzimología , Animales , Autoinmunidad/genética , Cruzamientos Genéticos , Hemo-Oxigenasa 1/deficiencia , Hemo-Oxigenasa 1/genética , Homeostasis/inmunología , Inmunidad Innata/genética , Integrasas/genética , Interferón beta/biosíntesis , Interferón beta/genética , Listeria monocytogenes , Listeriosis/inmunología , Listeriosis/mortalidad , Ratones , Ratones Noqueados , Ratones Transgénicos , Sobrevivientes , Receptor Toll-Like 3/inmunología , Receptor Toll-Like 4/inmunología
4.
Immunity ; 30(1): 130-42, 2009 Jan 16.
Artículo en Inglés | MEDLINE | ID: mdl-19119026

RESUMEN

Follicular dendritic cells (FDCs) are important for the induction of protective T cell-dependent humoral responses, but their contribution to autoimmunity remains elusive. Here, gene-targeted interruption of FDC development was combined with the K/BxN mouse model of arthritis. We found that FDCs were essential for autoantibody production through two distinct but cooperative functions. In a T cell-independent fashion, FDCs loaded with autoantigen-containing immune complexes supported germinal center (GC) B cell development. Additionally, the integrity of FDC networks was required for the recruitment of arthritogenic follicular helper T cells, a process that drove T-B cell interactions and productive GC reactivity. Importantly, pharmacological interference in the maintenance of FDCs ameliorated disease development, suggesting the FDC as a potential target for dampening autoimmunity.


Asunto(s)
Artritis/inmunología , Autoanticuerpos , Linfocitos B/inmunología , Células Dendríticas Foliculares/inmunología , Centro Germinal/inmunología , Memoria Inmunológica , Animales , Ratones , Ratones Transgénicos
5.
Immunity ; 24(1): 65-77, 2006 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-16413924

RESUMEN

The FDC-specific molecular signals required in the formation of FDC networks, B cell follicles, and germinal centers (GCs) have remained poorly understood. We used FDC-specific gene targeting to investigate the function of p55TNFR and IKK2 in lymphoid organ structure and function. Here we show that FDC-specific expression of p55TNFR is necessary and sufficient to promote FDC network and B cell follicle formation, restore the expression of CXCL13 and VCAM-1/ICAM-1 in FDCs, and lead to productive GCs. Notably, FDC-specific disruption of IKK2 does not affect formation of FDC networks. Yet, after antigen engagement or immune complex (IC) deposition, FDCs lacking IKK2 fail to upregulate VCAM-1 and ICAM-1, and GCs remain sterile. These findings demonstrate that IKK2-independent function of p55TNFR on FDCs is sufficient to support the development of FDC networks and GCs, while FDC-specific IKK2 is indispensable for the generation of efficient humoral immune responses.


Asunto(s)
Formación de Anticuerpos , Células Dendríticas Foliculares/inmunología , Quinasa I-kappa B/metabolismo , Receptores Tipo I de Factores de Necrosis Tumoral/metabolismo , Animales , Formación de Anticuerpos/genética , Apoptosis , Linfocitos B/citología , Linfocitos B/inmunología , Moléculas de Adhesión Celular/metabolismo , Quimiocina CXCL13 , Quimiocinas/genética , Quimiocinas/metabolismo , Quimiocinas CXC/genética , Quimiocinas CXC/metabolismo , Células Dendríticas Foliculares/citología , Células Dendríticas Foliculares/metabolismo , Marcación de Gen , Quinasa I-kappa B/genética , Inmunoglobulina G/inmunología , Molécula 1 de Adhesión Intercelular/genética , Molécula 1 de Adhesión Intercelular/metabolismo , Tejido Linfoide/citología , Tejido Linfoide/metabolismo , Ratones , Ratones Transgénicos , Receptores de Complemento 3d/genética , Receptores Tipo I de Factores de Necrosis Tumoral/genética , Factores de Transcripción/metabolismo , Regulación hacia Arriba , Molécula 1 de Adhesión Celular Vascular/genética , Molécula 1 de Adhesión Celular Vascular/metabolismo
6.
J Virol ; 78(23): 13253-61, 2004 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-15542676

RESUMEN

There is much evidence, based primarily on in vitro studies, indicating that the Epstein-Barr virus oncoprotein latent membrane protein 1 (LMP1) mimics an activated CD40 receptor. In order to investigate the extent of similarity between LMP1 and CD40 functions in vivo, we analyzed the cytoplasmic signaling properties of LMP1 and CD40 in B cells in a directly comparable manner. For this purpose, we generated transgenic mice expressing either LMP1 or a chimeric LMP1CD40 molecule, which constitutively activates the CD40 pathway, under the control of the CD19 promoter. LMP1 and LMP1CD40 were expressed at similar levels in a B-lymphocyte-specific manner. Similar to LMP1, LMP1CD40 suppressed germinal center (GC) formation and antibody production in response to thymus-dependent antigens, albeit to a greater extent than LMP1. Furthermore, the avidity of the antibodies produced against thymus-dependent antigens was lower for LMP1CD40 transgenic mice than for wild-type and LMP1 transgenic mice. GC suppression was linked to the ability of LMP1CD40 and LMP1 to downregulate mRNA and protein levels of BCL6 and to suppress the activity of the BCL6 promoter. In contrast to LMP1, LMP1CD40 caused an upregulation of CD69, CD80, and CD86 in B cells and a dramatic increase in serum immunoglobulin M. In addition, LMP1CD40 but not LMP1 transgenic mice had elevated numbers of marginal-zone B cells and increased populations of polymorphonuclear cells and/or neutrophils. Consistent with these findings, LMP1CD40 but not LMP1 transgenic mice showed signs of spontaneous inflammatory reactions and the potential for autoimmunity.


Asunto(s)
Antígenos CD40/fisiología , Transducción de Señal/fisiología , Proteínas de la Matriz Viral/fisiología , Animales , Autoinmunidad , Proteínas de Unión al ADN/análisis , Proteínas de Unión al ADN/genética , Centro Germinal/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteínas Proto-Oncogénicas/análisis , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas c-bcl-6 , Bazo/citología , Factores de Transcripción/análisis , Factores de Transcripción/genética
7.
Vet Microbiol ; 88(4): 325-38, 2002 Sep 24.
Artículo en Inglés | MEDLINE | ID: mdl-12220808

RESUMEN

Traditionally, adjuvants have been administered with antigens to enhance immunity. We studied the effect of several adjuvants such as Freund's complete adjuvant (FCA), Freund's incomplete adjuvant (FIA), lipopolysaccharide (LPS), homopolymers of polyinosinic-polycytidylic acid (poly I:C) and polyadenylic-polyuridylic acid (poly A:U), lithium chloride (LiCl), saponin Quil A and calcium phosphate gel (CaHPO(4)) on the immune response of mice to formalin-inactivated Mycoplasma agalactiae. The specific antibody or cytokine producing splenocytes were detected by ELISAspot and immunocytochemistry, respectively. Depending on the adjuvant given, the number of M. agalactiae-specific antibody producing cells was increased 2.5-6-fold. IgG was the major class of M. agalactiae-specific antibodies followed by IgM, IgA and IgE. Among IgG isotypes, FCA, FIA, Quil A and CaHPO(4) induced an IgG1 response with substantial increase of the IgG2a, IgG2b and IgG3 isotypes while poly I:C shifted the response toward an IgG2a/IgG3 production. Finally, poly A:U induced an IgG2b response while LPS and LiCl augmented the IgG3/IgG1/IgG2a secretion. FCA augmented IL-4, IL-5 and IL-10 production suggesting a strong Th2 response, while IFN-gamma and IL-12 remained low; poly I:C enhanced IFN-gamma, IL-12 and TNF-alpha eliciting a Th1 response; poly A:U resulted in a IL-10, IL-5, IL-6 and IL-12 secretion; and LPS enhanced the IL-10, IL-6 and TNF-alpha production. Our data show that adjuvants augment M. agalactiae-specific antibody production and lead to B cell isotype-switching via the appropriate cytokine milieu. Certain adjuvants, such as poly I:C, therefore, appear as promising immune enhancers for vaccination against M. agalactiae infections.


Asunto(s)
Adyuvantes Inmunológicos/farmacología , Citocinas/biosíntesis , Isotipos de Inmunoglobulinas/inmunología , Infecciones por Mycoplasma/inmunología , Mycoplasma/inmunología , Animales , Antígenos Bacterianos/biosíntesis , Antígenos Bacterianos/inmunología , Vacunas Bacterianas/inmunología , Vacunas Bacterianas/farmacología , Citocinas/metabolismo , Ensayo de Inmunoadsorción Enzimática , Inmunización/métodos , Cambio de Clase de Inmunoglobulina/inmunología , Isotipos de Inmunoglobulinas/biosíntesis , Inmunohistoquímica , Ratones , Ratones Endogámicos BALB C , Infecciones por Mycoplasma/metabolismo , Vacunas de Productos Inactivados/inmunología , Vacunas de Productos Inactivados/farmacología
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA
...