Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 5 de 5
Filtrar
1.
J Infect Dis ; 225(8): 1399-1410, 2022 04 19.
Artículo en Inglés | MEDLINE | ID: mdl-32313928

RESUMEN

BACKGROUND: A vaccine (HB-101) consisting of 2 nonreplicating lymphocytic choriomeningitis virus (LCMV) vectors expressing the human cytomegalovirus antigens glycoprotein B (gB) and the 65-kD phosphoprotein (pp65), respectively, is in development to prevent cytomegalovirus infection. METHODS: HB-101 was tested in cytomegalovirus-naive, healthy adults in a randomized, double-blind, placebo-controlled, dose-escalation Phase I trial. Fifty-four subjects received low, medium, or high dose of HB-101 or placebo by intramuscular administration at Month 0, 1, and 3. Safety and immunogenicity were the respective primary and secondary endpoints. Subjects were followed for 12 months after the initial immunization. RESULTS: Vaccination was associated with transient mild to moderate adverse events. HB-101 administration induced dose-dependent gB- and pp65-specific cellular responses, dominated by pp65-specific CD8 T cells, a high fraction of which were polyfunctional. Two administrations were sufficient to elicit dose-dependent gB-binding and cytomegalovirus-neutralizing antibodies (Abs). Cytomegalovirus-specific immune responses were boosted after each administration. Only 1 of 42 vaccine recipients mounted a transient LCMV vector-neutralizing Ab response. CONCLUSIONS: HB-101 was well tolerated and induced cytomegalovirus-specific polyfunctional CD8 T-cell and neutralizing Ab responses in the majority of subjects. Lack of vector-neutralizing Ab responses should facilitate booster vaccinations. These results justify further clinical evaluation of this vaccine candidate.


Asunto(s)
Vacunas contra Citomegalovirus , Vacunas , Adulto , Anticuerpos Neutralizantes , Anticuerpos Antivirales , Citomegalovirus/genética , Humanos , Inmunización Secundaria , Virus de la Coriomeningitis Linfocítica/genética
2.
Bioorg Med Chem Lett ; 20(15): 4515-20, 2010 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-20580552

RESUMEN

As a wide variety of pro-inflammatory cytokines are involved in the development of rheumatoid arthritis (RA), there is an urgent need for the discovery of novel therapeutic strategies. Among these, the inhibition of the NF-kappaB inducing kinase (NIK), a key enzyme of the NF-kappaB alternative pathway activation, represents a potential interesting approach. In fact, NIK is involved downstream of many tumor necrosis factor receptors (TNFR) like CD40, RANK or LTbetaR, implicated in the pathogenesis of RA. But, up to now, the number of reported putative NIK inhibitors is extremely limited. In this work, we report a virtual screening (VS) study combining various filters including high-throughput docking using a 3D-homology model and ranking by using different scoring functions. This work led to the identification of two molecular fragments, 4H-isoquinoline-1,3-dione (5) and 2,7-naphthydrine-1,3,6,8-tetrone (6) which inhibit NIK with an IC(50) value of 51 and 90 microM, respectively. This study opens new perspectives in the field of the NF-kappaB alternative pathway inhibition.


Asunto(s)
Inhibidores de Proteínas Quinasas/química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Artritis Reumatoide/tratamiento farmacológico , Sitios de Unión , Simulación por Computador , Humanos , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Recombinantes/antagonistas & inhibidores , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Quinasa de Factor Nuclear kappa B
3.
Cytokine Growth Factor Rev ; 22(5-6): 301-10, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-22152226

RESUMEN

This review focuses on the biological functions and signalling pathways activated by Lymphotoxin α (LTα)/Lymphotoxin ß (LTß) and their receptor LTßR. Genetic mouse models shed light on crucial roles for LT/LTßR to build and to maintain the architecture of lymphoid organs and to ensure an adapted immune response against invading pathogens. However, chronic inflammation, autoimmunity, cell death or cancer development are disorders that occur when the LT/LTßR system is twisted. Biological inhibitors, such as antagonist antibodies or decoy receptors, have been developed and used in clinical trials for diseases associated to the LT/LTßR system. Recent progress in the understanding of cellular trafficking and NF-κB signalling pathways downstream of LTα/LTß may bring new opportunities to develop therapeutics that target the pathological functions of these cytokines.


Asunto(s)
Heterotrímero de Linfotoxina alfa1 y beta2/inmunología , Receptor beta de Linfotoxina/inmunología , Linfotoxina-alfa/inmunología , Linfotoxina beta/inmunología , Animales , Muerte Celular , Expresión Génica , Humanos , Heterotrímero de Linfotoxina alfa1 y beta2/química , Receptor beta de Linfotoxina/química , Linfotoxina-alfa/química , Linfotoxina-alfa/genética , Linfotoxina beta/química , Linfotoxina beta/genética , FN-kappa B/inmunología , Estructura Terciaria de Proteína , Receptores Tipo I de Factores de Necrosis Tumoral/química , Receptores Tipo I de Factores de Necrosis Tumoral/inmunología , Receptores Tipo II del Factor de Necrosis Tumoral/química , Receptores Tipo II del Factor de Necrosis Tumoral/inmunología , Transducción de Señal
4.
Mol Cell Biol ; 31(21): 4319-34, 2011 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-21896778

RESUMEN

Several tumor necrosis factor receptor (TNFR) family members activate both the classical and the alternative NF-κB pathways. However, how a single receptor engages these two distinct pathways is still poorly understood. Using lymphotoxin ß receptor (LTßR) as a prototype, we showed that activation of the alternative, but not the classical, NF-κB pathway relied on internalization of the receptor. Further molecular analyses revealed a specific cytosolic region of LTßR essential for its internalization, TRAF3 recruitment, and p100 processing. Interestingly, we found that dynamin-dependent, but clathrin-independent, internalization of LTßR appeared to be required for the activation of the alternative, but not the classical, NF-κB pathway. In vivo, ligand-induced internalization of LTßR in mesenteric lymph node stromal cells correlated with induction of alternative NF-κB target genes. Thus, our data shed light on LTßR cellular trafficking as a process required for specific biological functions of NF-κB.


Asunto(s)
Heterotrímero de Linfotoxina alfa1 y beta2/metabolismo , Receptor beta de Linfotoxina/metabolismo , FN-kappa B/metabolismo , Animales , Secuencia de Bases , Transporte Biológico Activo , Cadenas Pesadas de Clatrina/antagonistas & inhibidores , Cadenas Pesadas de Clatrina/genética , Cadenas Pesadas de Clatrina/metabolismo , Citosol/metabolismo , Dinamina II/antagonistas & inhibidores , Dinamina II/genética , Dinamina II/metabolismo , Células HEK293 , Células HeLa , Humanos , Receptor beta de Linfotoxina/química , Receptor beta de Linfotoxina/deficiencia , Receptor beta de Linfotoxina/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Modelos Biológicos , Subunidad p52 de NF-kappa B/metabolismo , Procesamiento Proteico-Postraduccional , Proteínas Serina-Treonina Quinasas/metabolismo , ARN Interferente Pequeño/genética , Transducción de Señal , Factor 3 Asociado a Receptor de TNF/metabolismo , Factor de Transcripción ReIB/deficiencia , Factor de Transcripción ReIB/genética , Factor de Transcripción ReIB/metabolismo , Quinasa de Factor Nuclear kappa B
5.
Biochem Pharmacol ; 79(10): 1462-72, 2010 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-20096267

RESUMEN

In this work, we aimed to build a 3D-model of NIK and to study the binding of pyrazolo[4,3-c]isoquinolines with a view to highlight the structural elements responsible for their inhibitory potency. However, in the course of this work, we unexpectedly found that the pyrazolo[4,3-c]isoquinolines initially reported as NIK inhibitors were neither inhibitors of this enzyme nor of the alternative NF-kappaB pathway, but were in fact inhibitors of another kinase, the TGF-beta activated kinase 1 (TAK1) which is involved in the classical NF-kappaB pathway.


Asunto(s)
Isoquinolinas/antagonistas & inhibidores , FN-kappa B/antagonistas & inhibidores , Pirazoles/antagonistas & inhibidores , Artritis Reumatoide/metabolismo , Células HeLa , Humanos , Quinasas Quinasa Quinasa PAM/efectos de los fármacos , Quinasas Quinasa Quinasa PAM/fisiología , FN-kappa B/fisiología , Proteínas Recombinantes , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Relación Estructura-Actividad
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA