ES2537951T3 - Aislamiento e identificación de células T - Google Patents
Aislamiento e identificación de células T Download PDFInfo
- Publication number
- ES2537951T3 ES2537951T3 ES03784936.1T ES03784936T ES2537951T3 ES 2537951 T3 ES2537951 T3 ES 2537951T3 ES 03784936 T ES03784936 T ES 03784936T ES 2537951 T3 ES2537951 T3 ES 2537951T3
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- Prior art keywords
- cells
- activated
- cell
- antibody
- antigen
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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Abstract
Un método para aislar una o más células T autólogas y específicas para un antígeno de interés de un paciente, que comprende: (a) incubar una muestra que comprende células T obtenidas de dicho paciente con dicho antígeno o un derivado del mismo que conserva la capacidad de provocar una respuesta inmunitaria; (b) aislar células T específicas para dicho antígeno identificando células que expresan uno o más primeros marcadores seleccionados entre el grupo constituido por CD69, CD4, CD25, CD36 y HLADR y uno o más segundos marcadores seleccionados entre el grupo constituido por IL-2, IFNg, TNFa, IL-5, IL-10 e IL-13.
Description
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El producto génico para identificar o seleccionar negativamente células T activadas puede ser un marcador de la superficie celular o citoquina, o una combinación de los mismos. Los marcadores de la superficie celular para identificar células T activadas incluyen, aunque no se limitan a, CD69, CD4, CD8, CD25, HLA-DR, CD28 y CD 134. CD69 es un marcador de activación temprana que se encuentra en linfocitos B y T, células NK y granulocitos. CD25 es un receptor de IL-2 y es un marcador para células T activadas y células B. CD4 es un correceptor de TCR y es marcador para timocitos, células T de tipo TH1 y TH2, monocitos y macrófagos. CD8 es también un correceptor de TCR y es marcador para células T citotóxicas. CD 134 se expresa solamente en células T CD4+ activadas.
Los marcadores de la superficie celular para seleccionar negativamente células T activadas incluyen, aunque no se limitan a, CD36, CD40 y CD44. CD28 actúa como una ruta de activación de células T estimuladoras independiente de la ruta del receptor de células T y se expresa en células CD4+ y CD8+. CD36 es una glucoproteína de membrana y es marcador para plaquetas, monocitos y células endoteliales. CD40 es un marcador para células B, macrófagos y células dendríticas. CD44 es un marcador para macrófagos y otras células fagocíticas. Pueden aislarse subconjuntos de células T usando selección positiva, selección negativa, o una combinación de las mismas para la expresión de productos génicos de la superficie celular de células T cooperadoras o células T citotóxicas (por ejemplo, CD4 frente a CD8).
Las citoquinas para identificar células T activadas de la presente invención incluyen, aunque no se limitan a, citoquinas producidas por células T de tipo TH1 (respuesta mediada por células) y células t de tipo TH2 (respuesta de anticuerpos). Las citoquinas para identificar células T de tipo TH1 activadas incluyen, aunque no se limitan a, IL-2, interferón gamma (γIFN) y factor de necrosis tisular alfa (TNFα). Las citoquinas para identificar células T de tipo TH2 activadas incluyen, aunque sin limitarse a, IL-4, IL-5, IL-10 y IL-13. También pueden aislarse subconjuntos de células T usando selección positiva, selección negativa, o una combinación de las mismas para expresión de productos génicos de citoquinas de células T cooperadoras o células T citotóxicas (por ejemplo, γIFN frente a IL4).
Una célula T de tipo TH1 activada específica para un antígeno de interés puede aislarse identificando células que expresan CD69, CD4, CD25, IL-2, IFNγ, TNFα, o una combinación de los mismos. Una célula T de tipo TH1 activada específica para un antígeno de interés también puede aislarse identificando células que expresan CD69 y CD4 junto con IFNγ o TNFα. Una célula T de tipo TH2 activada específica para un antígeno de interés puede aislarse identificando células que expresan CD69, CD4, IL-4, IL-5, IL-10, IL-13, o una combinación de los mismos. Una combinación de una célula T de tipo TH1 activada y una célula T de tipo TH2 específica para un antígeno de interés puede aislarse identificando células que expresan CD69, CD4, CD25, IL-2, IFNγ, TNFα, o una combinación de los mismos y células que expresan CD69, CD4, IL-4, IL-5, IL-10, IL-13, o una combinación de los mismos.
Los productos génicos usados para la selección positiva o negativa de las células T activadas pueden identificarse mediante técnicas de inmunoselección conocidas por los expertos en la materia que utilizan anticuerpos incluyendo, aunque sin limitarse a, separación de células activadas por fluorescencia (FACS), separación de células magnéticas, inmunopurificación (“panning”), y cromatografía. La inmunoselección de dos o más marcadores en células T activadas puede realizarse en una o más etapas, en la que cada etapa selecciona positiva o negativamente uno o más marcadores. Cuando se realiza inmunoselección de dos o más marcadores en una etapa usando FACS, los dos o más anticuerpos diferentes pueden marcarse con diferentes fluoróforos.
La separación de células magnéticas puede realizarse usando microperlas super-paramagnéticas compuestas por óxido de hierro y un revestimiento polisacarídico. Preferentemente las microperlas pueden ser de aproximadamente 50 nanómetros de diámetro, y tener un volumen de aproximadamente una millonésima la de una célula de mamífero típica. Las microperlas son, preferentemente, lo suficientemente pequeñas para permanecer en suspensión coloidal, que permite la unión rápida y eficiente a antígenos de la superficie celular. Las microperlas preferentemente no interfieren en la citometría de flujo, son biodegradables, y tienen efectos insignificantes sobre las funciones celulares. El anticuerpo que se acopla a las microperlas puede ser directo o indirecto, mediante un segundo anticuerpo para un ligando, tal como fluoresceína.
El anticuerpo puede ser de las clases IgG, IgM, IgA, IgD e IgE, o fragmentos o derivados de los mismos, incluyendo Fab, F(ab')2, Fd, y anticuerpos monocatenarios, diacuerpos, anticuerpos biespecíficos, anticuerpos bifuncionales y derivados de los mismos. El anticuerpo puede ser un anticuerpo monoclonal, anticuerpo policlonal, anticuerpo purificado por afinidad, o mezclas de los mismos que muestra suficiente especificidad de unión a un epítopo de un producto génico específico para células T activadas, o una secuencia derivada de él. El anticuerpo también puede ser un anticuerpo quimérico.
El anticuerpo puede derivatizarse mediante la fijación de una o más fracciones químicas, peptídicas o polipeptídicas conocidas en la técnica que permiten la identificación y/o selección de la célula T activada, a la que está unido el anticuerpo. El anticuerpo puede estar conjugado con una fracción química tal como un colorante fluorescente. Una célula T activada a la que está unido un anticuerpo marcado de forma fluorescente puede aislarse usando técnicas que incluyen, aunque sin limitarse a, separación de células activadas por fluorescencia (FACS). El anticuerpo también puede conjugarse con una partícula magnética, tal como una perla paramagnética (Miltenyi Biotec, Alemania). Una célula T activada a la que está unido un anticuerpo marcado de forma magnética puede aislarse
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intervalos de dosis para la administración de las composiciones farmacéuticas pueden ser lo suficientemente grandes para producir el efecto deseado, con lo que, por ejemplo, la reducción del número de células T autorreactivas, según lo medido mediante el séptimo aspecto de la presente invención, se consigue, y la enfermedad autoinmunitaria se previene, suprime o trata significativamente. Las dosis pueden no ser tan grandes como para causar efectos secundarios adversos, tales como reacciones cruzadas no deseadas, inmunosupresión generalizada, reacciones anafilácticas y similares.
Las composiciones farmacéuticas pueden comprender además portadores farmacéuticamente aceptables adecuados que comprenden excipientes y auxiliares que pueden facilitar el procesamiento de las composiciones activas en preparaciones que pueden usarse de forma farmacéutica. Los aditivos para las composiciones farmacéuticas pueden incluir la inclusión de un adyuvante, tal como alumbre, quitosano, u otros adyuvantes conocidos en la técnica. (Véase, por ejemplo, los documentos Warren et al., Ann. Rev. Immunol. 4: 369-388 (1986); Chedid, L., Feder. Proc. 45: 2531-2560 (1986), que se incorporan en el presente documento como referencia). Las composiciones farmacéuticas también pueden comprender además liposomas para intensificar el suministro o la bioactividad, usando métodos y compuestos conocidos en la técnica.
Las formulaciones adecuadas para administración parenteral incluyen soluciones acuosas de las células T autorreactivas inactivadas, por ejemplo, sales solubles en agua en solución acuosa. Además, pueden administrarse suspensiones oleosas que comprenden células T autorreactivas inactivadas. Los disolventes o vehículos lipófilos adecuados incluyen aceites grasos, por ejemplo, aceite de sésamo, o ésteres de ácidos grasos sintéticos, por ejemplo, oleato de etilo o triglicéridos. Las suspensiones acuosas para inyección pueden contener sustancias que incrementan la viscosidad de la suspensión e incluyen, por ejemplo, carboximetilcelulosa sódica, sorbitol y/o dextrano. La suspensión también puede contener estabilizantes.
Las células T autorreactivas inactivadas pueden formularse usando vehículos parenterales farmacéuticamente aceptables convencionales para administración por inyección. Estos vehículos pueden ser no tóxicos y terapéuticos, y una serie de formulaciones se exponen en el documento Remington's Pharmaceutical Sciences, (supra). Son ejemplos no limitantes de excipientes agua, solución salina, solución de Ringer, solución de dextrosa y solución salina equilibrada de Hank. Las composiciones farmacéuticas también pueden contener cantidades secundarias de aditivos tales como sustancias que mantienen la isotonicidad, el pH fisiológico y la estabilidad.
Las células T autorreactivas inactivadas pueden formularse a concentraciones de células totales que incluyen de aproximadamente 5x102 células/ml a aproximadamente 1x109 células/ml. Las dosis preferidas de las células T autorreactivas inactivadas para uso en la prevención, la supresión o el tratamiento de una enfermedad autoinmunitaria pueden estar en el intervalo de aproximadamente 2x106 células a aproximadamente 9x107 células.
8. Determinación del repertorio de TCR
También se desvela un método de determinación del repertorio de ácidos nucleicos que codifican uno o más receptores de células T, o una parte de los mimos, en un paciente autoinmunitario amplificando ácidos nucleicos que codifican uno o más receptores de células T a partir de células T asiladas mediante 2a o 2c, en el que dicha amplificación se realiza usando un par de cebadores. El primer cebador del par de cebadores puede ser un oligonucleótido de aproximadamente 15 a 30 nucleótidos de longitud que hibrida con un ácido nucleico que comprende la región variable del gen de TCR. El segundo cebador del par de cebadores puede ser un oligonucleótido de aproximadamente 15 a 30 nucleótidos de longitud que hibrida con un ácido nucleico que comprende la región constante del gen de TCR. El par de cebadores puede usarse para amplificar un ácido nucleico que hibrida con la región Vβ-Dβ-Jβ del gen de TCR.
Ácidos nucleicos que codifican uno o más receptores de células T a partir de células T (la “secuencia diana”) o un fragmento de los mismos pueden amplificarse a partir de una muestra mediante la reacción en cadena de la polimerasa (PCR) usando cualquier técnica o equipo de PCR particular conocido en la técnica. Por ejemplo, la amplificación por PCR puede seguir un procedimiento en el que se prepara una mezcla de reacción que contiene los siguientes ingredientes: 5 µl de 10xtampón de PCR II (Tris-HCl 100 mM, pH 8,3, KCl 500 mM), 3 µl de MgCl2 25 mM, 1 µl de mezcla de dNTP 10 mM, 0,3 µl de Taq polimerasa (5 U/µl) (AmpliTaq Gold, Pekin Elmer, Norwalk, Conn.), 30 pmoles de un primer cebador, 30 pmoles de un segundo cebador, y 1 µl de ADN de muestra. La polimerasa puede ser estable a temperaturas de al menos 95 °C, tener una capacidad de procesamiento de 50-60 y tener una tasa de extensión de más de 50 nucleótidos por minuto.
La reacción de PCR puede realizarse con un perfil de amplificación de 1 minuto a 95 °C (desnaturalización), 20 segundos a 56 °C (hibridación), y 40 segundos a 72 °C (extensión) durante un total de 40 ciclos. Antes de que comience el primer ciclo, la mezcla de reacción puede experimentar una desnaturalización inicial durante un periodo de aproximadamente 5 minutos a 15 minutos. Análogamente, después de que el ciclo final está completo, la mezcla de reacción puede experimentar una extensión final durante un periodo de aproximadamente 5 minutos a 10 minutos. Algunas reacciones de PCR pueden funcionar con tan solo de 15 a 20 ciclos o hasta 50 ciclos. Dependiendo de la reacción de PCR específica, pueden usarse tiempos de incubación más largos o más cortos y temperaturas más altas o más bajas para cada etapa del perfil de amplificación.
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- 2003-08-06 EP EP10182296.3A patent/EP2363710B1/en not_active Expired - Lifetime
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