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1.
Cell Rep ; 35(6): 109112, 2021 05 11.
Artículo en Inglés | MEDLINE | ID: mdl-33979622

RESUMEN

Receptor interacting protein kinase 1 (RIPK1) mediates cell death and inflammatory signaling and is increased in multiple sclerosis (MS) brain samples. Here, we investigate the role of glial RIPK1 kinase activity in mediating MS pathogenesis. We demonstrate RIPK1 levels correlate with MS disease progression. We find microglia are susceptible to RIPK1-mediated cell death and identify an inflammatory gene signature that may contribute to the neuroinflammatory milieu in MS patients. We uncover a distinct role for RIPK1 in astrocytes in regulating inflammatory signaling in the absence of cell death and confirm RIPK1-kinase-dependent regulation in human glia. Using a murine MS model, we show RIPK1 inhibition attenuates disease progression and suppresses deleterious signaling in astrocytes and microglia. Our results suggest RIPK1 kinase activation in microglia and astrocytes induces a detrimental neuroinflammatory program that contributes to the neurodegenerative environment in progressive MS.


Asunto(s)
Microglía/metabolismo , Esclerosis Múltiple/genética , Enfermedades Neuroinflamatorias/genética , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismo , Animales , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Humanos , Ratones , Esclerosis Múltiple/patología , Transducción de Señal
2.
J Neuroimmunol ; 285: 4-12, 2015 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-26198912

RESUMEN

Alemtuzumab, a monoclonal antibody directed against human CD52, is used in the treatment of MS. To characterize the impact of anti-CD52 administration, a monoclonal antibody to mouse CD52 (anti-muCD52) was generated and evaluated in EAE mouse models of MS. A single course of anti-muCD52 provided a therapeutic benefit accompanied by a reduction in the frequency of autoreactive T lymphocytes and production of pro-inflammatory cytokines. Examination of the CNS revealed a decrease in infiltrating lymphocytes, demyelination and axonal loss. Electrophysiological assessment showed preservation of axonal conductance in the spinal cord. These findings suggest that anti-CD52 therapy may help preserve CNS integrity.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antígenos CD/inmunología , Antígenos de Neoplasias/inmunología , Enfermedades Desmielinizantes/tratamiento farmacológico , Enfermedades Desmielinizantes/inmunología , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Encefalomielitis Autoinmune Experimental/inmunología , Glicoproteínas/inmunología , Secuencia de Aminoácidos , Animales , Anticuerpos Monoclonales/genética , Anticuerpos Monoclonales/farmacología , Axones/efectos de los fármacos , Axones/inmunología , Axones/patología , Antígeno CD52 , Enfermedades Desmielinizantes/patología , Encefalomielitis Autoinmune Experimental/patología , Glicoproteínas/antagonistas & inhibidores , Humanos , Inflamación/tratamiento farmacológico , Inflamación/inmunología , Inflamación/patología , Mediadores de Inflamación/antagonistas & inhibidores , Mediadores de Inflamación/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Datos de Secuencia Molecular
3.
J Neuroimmunol ; 261(1-2): 29-36, 2013 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-23759318

RESUMEN

Alemtuzumab is a monoclonal antibody against the CD52 antigen present at high levels on the surface of lymphocytes. While treatment of multiple sclerosis patients with alemtuzumab results in marked depletion of lymphocytes from the circulation, it has not been associated with a high incidence of serious infections. In a human CD52 transgenic mouse, alemtuzumab treatment showed minimal impact on the number and function of innate immune cells. A transient decrease in primary adaptive immune responses was observed post-alemtuzumab but there was little effect on memory responses. These results potentially help explain the level of immunocompetence observed in alemtuzumab-treated MS patients.


Asunto(s)
Inmunidad Adaptativa/genética , Anticuerpos Monoclonales Humanizados/fisiología , Antígenos CD/inmunología , Antígenos de Neoplasias/inmunología , Glicoproteínas/inmunología , Alemtuzumab , Animales , Antígenos CD/genética , Antígenos de Neoplasias/genética , Linfocitos B/inmunología , Antígeno CD52 , Células Cultivadas , Glicoproteínas/genética , Humanos , Inmunidad Innata/genética , Ratones , Ratones Transgénicos , Linfocitos T/inmunología , Resultado del Tratamiento
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