RESUMEN
BACKGROUND AND PURPOSE: Very late antigen-4 (integrin α4ß1)/vascular cell adhesion molecule-1 mediates leukocyte trafficking and transendothelial migration after stroke. Mesenchymal stem cells (MSCs) typically express integrin ß1 but insufficient ITGA4 (integrin α4), which limits their homing after intravascular transplantation. We tested whether ITGA4 overexpression on MSCs increases cerebral homing after intracarotid transplantation and reduces MSC-borne cerebral embolism. METHODS: Rat MSCs were lentivirally transduced to overexpress ITGA4. In vitro transendothelial migration was assessed using a Boyden chamber assay. Male Wistar rats intracarotidly received 0.5×106 control or modified MSCs 24 hours after sham or stroke surgery. In vivo behavior of MSCs in the cerebral vasculature was observed by intravital microscopy and single-photon emission computed tomography for up to 72 hours. RESULTS: Transendothelial migration of ITGA4-overexpressing MSCs was increased in vitro. MSCs were passively entrapped in microvessels in vivo and occasionally formed large cell aggregates causing local blood flow interruptions. MSCs were rarely found in perivascular niches or parenchyma at 72 hours post-transplantation, but ITGA4 overexpression significantly decreased cell aggregation and ameliorated the evoked cerebral embolism in stroke rats. CONCLUSIONS: ITGA4 overexpression on MSCs enhances transendothelial migration in vitro, but not in vivo, although it improves safety after intracarotid transplantation into stroke rats.
Asunto(s)
Integrina alfa4/administración & dosificación , Integrina alfa4/biosíntesis , Embolia Intracraneal/terapia , Células Madre Mesenquimatosas/metabolismo , Trasplante de Células Madre/métodos , Migración Transendotelial y Transepitelial/fisiología , Animales , Células Cultivadas , Expresión Génica , Inyecciones Intraarteriales , Integrina alfa4/genética , Embolia Intracraneal/diagnóstico por imagen , Masculino , Ratas , Ratas WistarRESUMEN
Revisar y actualizar la información sobre el mecanismo de acción del natalizumab y su eficacia en el tratamientode la esclerosis múltiple (EM). Desarrollo. El natalizumab, un anticuerpo humanizado monoclonal frente a la integrina alfa-4, se une a su receptor en la superficie de los linfocitos e impide la transmigración de éstos a las zonas inflamadasdel tejido cerebral. Además, parece que el natalizumab disminuye la activación de los linfocitos T que ocurre tras su infiltración en el parénquima cerebral y puede contribuir a la apoptosis de los linfocitos T en estos tejidos. Se han llevado a cabo dosgrandes ensayos clínicos multicéntricos de dos años de duración (AFFIRM y SENTINEL), que demuestran una eficacia superior a la conocida hasta ahora en la prevención de las recaídas y de la progresión de la EM. El natalizumab redujo la frecuencia anual de las recaídas en un 68 y 54% en estos ensayos respectivamente (p < 0,001). Además, también disminuyó significativamenteel riesgo de progresión de la discapacidad en un 42 y un 24%, respectivamente. Según los resultados del estudioAFFIRM, los acontecimientos adversos que fueron significativamente más frecuentes en el grupo tratado con natalizumab que en el grupo placebo fueron la fatiga (27 frente a 21%) y las reacciones alérgicas (9 frente a 4%). La incidencia de reaccionesde hipersensibilidad graves descritas como anafilácticas o anafilactoides fue baja (< 1%) y respondieron adecuadamente al tratamiento habitual. En el estudio SENTINEL se diagnosticaron dos casos de leucoencefalopatía multifocal progresiva(LMP), uno de ellos mortal, en el grupo tratado con natalizumab asociado a interferón beta-1a. Conclusiones. El natalizumab ha demostrado reducir el riesgo de progresión sostenida de discapacidad y la frecuencia de recaídas clínicamente detectadas en pacientes con EM remitente recurrente. A pesar de su bajo riesgo de producción de reacciones adversas, debe vigilarse alos pacientes tratados con natalizumab a intervalos regulares para detectar cualquier aparición o empeoramiento de signos o síntomas neurológicos que pudieran ser indicativos de LMP, y su empleo debe restringirse a las indicaciones aprobadas
To review and update the mechanism of action of natalizumab and its efficacy in the treatment of multiplesclerosis (MS). Development. Natalizumab, an anti-alfa-4 integrin monoclonal humanized antibody, binds to lymphocyte surface receptors to prevent transmigration of lymphocytes to areas of inflammation into the brain tissue. Furthermore, natalizumab appears to reduce T-cell activation following their infiltration of the brain parenchyma and may contribute toT-cell apoptosis in these tissues. Two large two-year, multicenter phase III trials (AFFIRM and SENTINEL) have been completed and demonstrate previously unseen efficacy in preventing MS relapses and disease progression. Natalizumabreduced the rate of clinical relapse at one year by 68 and 54% respectively in these trials (p < 0.001). Moreover, natalizumab reduced significantly the risk of sustained progression of disability by 42 and 24% respectively. Based on results from theAFFIRM study, the adverse events that were significantly more frequent in the natalizumab group than in the placebo group were fatigue (27 vs. 21%) and allergic reaction (9 vs. 4%). There was a low incidence (< 1%) of serious systemic hypersensitivityreactions described as anaphylactoid or anaphylactic, and they appear to be effectively managed by post-treatment observation and by timely and appropriate medical treatment. In the SENTINEL study, two cases of progressive multifocal leukoencephalopathy (PML), one of which was fatal, were diagnosed in natalizumab plus interferon beta-1a treated patients.Conclusions. Natalizumab reduced the risk of the sustained progression of disability and the rate of clinical relapse in patients with relapsing MS. In spite of their low risk of adverse reactions, patients must be monitored at regular intervals for any newor worsening neurological symptoms or signs that may be suggestive of PML, and natalizumab use must be restricted to the indicated patients
