RESUMEN
We have previously described critical and nonredundant roles for the phosphoinositide 3-kinase p110delta during the activation and differentiation of naive T cells, and p110delta inhibitors are currently being developed for clinical use. However, to effectively treat established inflammatory or autoimmune diseases, it is important to be able to inhibit previously activated or memory T cells. In this study, using the isoform-selective inhibitor IC87114, we show that sustained p110delta activity is required for interferon-gamma production. Moreover, acute inhibition of p110delta inhibits cytokine production and reduces hypersensitivity responses in mice. Whether p110delta played a similar role in human T cells was unknown. Here we show that IC87114 potently blocked T-cell receptor-induced phosphoinositide 3-kinase signaling by both naive and effector/memory human T cells. Importantly, IC87114 reduced cytokine production by memory T cells from healthy and allergic donors and from inflammatory arthritis patients. These studies establish that previously activated memory T cells are at least as sensitive to p110delta inhibition as naive T cells and show that mouse models accurately predict p110delta function in human T cells. There is therefore a strong rationale for p110delta inhibitors to be considered for therapeutic use in T-cell-mediated autoimmune and inflammatory diseases.
Asunto(s)
Linfocitos T CD4-Positivos/enzimología , Linfocitos T CD4-Positivos/inmunología , Citocinas/biosíntesis , Inmunidad/inmunología , Fosfatidilinositol 3-Quinasas/metabolismo , Adenina/análogos & derivados , Adenina/farmacología , Animales , Artritis/enzimología , Artritis/inmunología , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Fosfatidilinositol 3-Quinasa Clase I , Humanos , Hipersensibilidad/enzimología , Hipersensibilidad/inmunología , Inmunidad/efectos de los fármacos , Memoria Inmunológica/efectos de los fármacos , Memoria Inmunológica/inmunología , Activación de Linfocitos/efectos de los fármacos , Ratones , Inhibidores de las Quinasa Fosfoinosítidos-3 , Quinazolinas/farmacología , Receptores de Antígenos de Linfocitos T/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
The SAR and pharmacokinetic profiles of a series of multi-isoform PI3K inhibitors based on a 3,4-dihydro-2H-benzo[1,4]oxazine scaffold are disclosed.
Asunto(s)
Benzoxazinas/química , Química Farmacéutica/métodos , Oxazinas/síntesis química , Oxazinas/farmacología , Fosfatidilinositol 3-Quinasas/metabolismo , Área Bajo la Curva , Benzoxazinas/farmacología , Cristalografía por Rayos X/métodos , Diseño de Fármacos , Humanos , Inflamación , Concentración 50 Inhibidora , Modelos Químicos , Estructura Molecular , Isoformas de Proteínas , Relación Estructura-ActividadRESUMEN
Increasing evidence suggests that peripheral inflammatory responses to stroke and other brain injuries have an important role in determining neurological outcome. The mediators of this response and the temporal relationships between peripheral and central inflammatory alterations are poorly understood. In this study, we show that experimental stroke in mice induces a peripheral inflammatory response that peaks 4 h after stroke, and precedes the peak in brain inflammation 24 h after stroke. This peripheral response is dominated by the induction of the chemokine CXCL-1 and the proinflammatory cytokine interleukin-6 and could serve as an accessible target for therapy and as a source of biomarkers predictive of prognosis.