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1.
Proc Natl Acad Sci U S A ; 110(5): 1941-6, 2013 Jan 29.
Artículo en Inglés | MEDLINE | ID: mdl-23322736

RESUMEN

Alzheimer's disease (AD) is the most common cause of dementia worldwide. The pathogenesis of this neurodegenerative disease, currently without curative treatment, is associated with the accumulation of amyloid ß (Aß) in brain parenchyma and cerebral vasculature. AD patients are unable to clear this toxic peptide, leading to Aß accumulation in their brains and, presumably, the pathology associated with this devastating disease. Compounds that stimulate the immune system to clear Aß may therefore have great therapeutic potential in AD patients. Monophosphoryl lipid A (MPL) is an LPS-derived Toll-like receptor 4 agonist that exhibits unique immunomodulatory properties at doses that are nonpyrogenic. We show here that repeated systemic injections of MPL, but not LPS, significantly improved AD-related pathology in APP(swe)/PS1 mice. MPL treatment led to a significant reduction in Aß load in the brain of these mice, as well as enhanced cognitive function. MPL induced a potent phagocytic response by microglia while triggering a moderate inflammatory reaction. Our data suggest that the Toll-like receptor 4 agonist MPL may be a treatment for AD.


Asunto(s)
Enfermedad de Alzheimer/prevención & control , Encéfalo/efectos de los fármacos , Lípido A/análogos & derivados , Receptor Toll-Like 4/agonistas , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Western Blotting , Encéfalo/metabolismo , Encéfalo/patología , Línea Celular , Citocinas/genética , Citocinas/metabolismo , Expresión Génica/efectos de los fármacos , Células HEK293 , Humanos , Inmunidad Innata/efectos de los fármacos , Ligandos , Lípido A/administración & dosificación , Lípido A/uso terapéutico , Lipopolisacáridos/farmacología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Microglía/citología , Microglía/efectos de los fármacos , Microglía/metabolismo , Microscopía Fluorescente , Fagocitosis/efectos de los fármacos , Presenilina-1/genética , Presenilina-1/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Receptor Toll-Like 4/metabolismo
2.
J Immunol Methods ; 424: 64-79, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-26002154

RESUMEN

Antibody-mediated capture of amyloid-beta (Aß) in peripheral blood was identified as an attractive strategy to eliminate cerebral toxic amyloid in Alzheimer's disease (AD) patients and murine models. Alternatively, defective capacity of peripheral monocytes to engulf Aß was reported in individuals with AD. In this report, we developed different approaches to investigate cellular uptake and phagocytosis of Aß, and to examine how two immunological devices--an immunostimulatory Adjuvant System and different amyloid specific antibodies--may affect these biological events. Between one and thirteen months of age, APPswe X PS1.M146V (TASTPM) AD model mice had decreasing concentrations of Aß in their plasma. In contrast, the proportion of blood monocytes containing Aß tended to increase with age. Importantly, the TLR-agonist containing Adjuvant System AS01B primed monocytes to promote de novo Aß uptake capacity, particularly in the presence of anti-Aß antibodies. Biochemical experiments demonstrated that cells achieved Aß uptake and internalization followed by Aß degradation via mechanisms that required effective actin polymerization and proteolytic enzymes such as insulin-degrading enzyme. We further demonstrated that both Aß-specific monoclonal antibodies and plasma from Aß-immunized mice enhanced the phagocytosis of 1 µm Aß-coated particles. Together, our data highlight a new biomarker testing to follow amyloid clearance within the blood and a mechanism of Aß uptake by peripheral monocytes in the context of active or passive immunization, and emphasize on novel approaches to investigate this phenomenon.


Asunto(s)
Péptidos beta-Amiloides/metabolismo , Monocitos/inmunología , Monocitos/metabolismo , Fagocitosis/inmunología , Actinas/metabolismo , Adyuvantes Inmunológicos , Enfermedad de Alzheimer/inmunología , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/terapia , Péptidos beta-Amiloides/sangre , Péptidos beta-Amiloides/inmunología , Animales , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/metabolismo , Encéfalo/inmunología , Encéfalo/metabolismo , Encéfalo/patología , Línea Celular , Modelos Animales de Enfermedad , Combinación de Medicamentos , Inmunofenotipificación , Inmunoterapia , Lípido A/administración & dosificación , Lípido A/análogos & derivados , Lípido A/inmunología , Ratones , Ratones Transgénicos , Multimerización de Proteína , Proteolisis , Saponinas/administración & dosificación , Saponinas/inmunología , Vacunación
3.
Clin Vaccine Immunol ; 19(2): 209-18, 2012 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-22190392

RESUMEN

Influenza A/H3N2 viruses have caused the most severe epidemics since 1968 despite current immunization programs with inactivated vaccines. We undertook a side-by-side preclinical evaluation of different adjuvants (Alum, AS03, and Protollin) and routes of administration (intramuscular [i.m.] and intranasal [i.n.]) for assessing their effect on the immunogenicity and cross-reactivity of inactivated split vaccines (A/H3N2/New York/55/2004). Humoral and T cell-mediated immune responses against the homologous virus and a heterologous drifted strain (A/H3N2/Wisconsin/67/2005) were measured in BALB/c mice at 2, 6, and 19 weeks postboost. The AS03- and Alum-adjuvanted i.m. vaccines induced at least an 8-fold increase over the nonadjuvanted vaccine in functional antibody titers against both the homotypic and heterotypic strains and low IgG2a and high IgG1 levels, suggesting a mixed Th1/Th2 response with a Th2 trend. The Protollin-adjuvanted i.n. vaccine induced the lowest IgG1/IgG2a ratio, which is indicative of a mixed Th1/Th2-type profile with a Th1 trend. This adjuvanted vaccine was the only vaccine to stimulate a mucosal IgA response. Whatever the timing after the boost, both hemagglutination inhibition (HAI) and microneutralization (MN) titers were higher with the AS03-adjuvanted i.m. vaccine than with the protollin-adjuvanted i.n. vaccine. Finally, the Alum-adjuvanted i.m. vaccine and the lower-dose Protollin-adjuvanted i.n. vaccine elicited significantly higher CD4(+) Th1 and Th2 responses and more gamma interferon (IFN-γ)-producing CD8(+) T cells than the nonadjuvanted vaccine. Our data indicate that the adjuvanted vaccines tested in this study can elicit stronger, more persistent, and broader immune responses against A/H3N2 strains than nonadjuvanted inactivated influenza vaccines.


Asunto(s)
Adyuvantes Inmunológicos/farmacología , Subtipo H3N2 del Virus de la Influenza A/inmunología , Vacunas contra la Influenza/inmunología , Infecciones por Orthomyxoviridae/prevención & control , Adyuvantes Inmunológicos/administración & dosificación , Administración Intranasal , Compuestos de Alumbre/administración & dosificación , Compuestos de Alumbre/farmacología , Animales , Anticuerpos Antivirales/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Cisteína Endopeptidasas/administración & dosificación , Cisteína Endopeptidasas/inmunología , Combinación de Medicamentos , Evaluación Preclínica de Medicamentos , Pruebas de Inhibición de Hemaglutinación , Inmunidad Celular , Inmunidad Humoral , Inmunoglobulina A/inmunología , Inmunoglobulina G/inmunología , Vacunas contra la Influenza/administración & dosificación , Inyecciones Intramusculares , Interferón gamma/inmunología , Lipopolisacáridos/administración & dosificación , Lipopolisacáridos/inmunología , Ratones , Ratones Endogámicos BALB C , Infecciones por Orthomyxoviridae/inmunología , Células TH1/inmunología , Células Th2/inmunología , Vacunación/métodos
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