RESUMO
Asthma is a heterogeneous disease characterized by airway inflammation and hyperreactivity. IL-17 receptor A (IL-17RA) is a shared receptor subunit required for activity of IL-17 family cytokines, including IL-17A and IL-25. IL-17A and IL-25 induce different proinflammatory responses, and concentrations are elevated in subjects with asthma. However, the individual contributions of IL-17A and IL-25 to disease pathogenesis are unclear. We explored proinflammatory activities of the IL-17 pathway in models of pulmonary inflammation and assessed its effects on contractility of human bronchial airway smooth muscle. In two mouse models, IL-17RA, IL-17RB, or IL-25 blockade reduced airway inflammation and airway hyperreactivity. Individually, IL-17A and IL-25 enhanced contractility of human bronchial smooth muscle induced by methacholine or carbachol. IL-17A had more pronounced effects on methacholine-induced contractility in bronchial rings from donors with asthma compared with donors without asthma. Blocking the IL-17 pathway via IL-17RA may be a useful therapy for some patients with asthma by reducing pulmonary inflammation and airway hyperreactivity.
Assuntos
Asma/metabolismo , Receptores de Interleucina-17/fisiologia , Animais , Asma/imunologia , Brônquios/imunologia , Brônquios/patologia , Células Cultivadas , Expressão Gênica , Humanos , Interleucina-17/fisiologia , Interleucinas/fisiologia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Contração Muscular , Miócitos de Músculo Liso/imunologia , Miócitos de Músculo Liso/metabolismo , Transdução de SinaisRESUMO
The development and optimization of a series of quinolinylpurines as potent and selective PI3Kδ kinase inhibitors with excellent physicochemical properties are described. This medicinal chemistry effort led to the identification of 1 (AMG319), a compound with an IC50 of 16 nM in a human whole blood assay (HWB), excellent selectivity over a large panel of protein kinases, and a high level of in vivo efficacy as measured by two rodent disease models of inflammation.
Assuntos
Adenosina/farmacologia , Doenças Autoimunes/prevenção & controle , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Inflamação/prevenção & controle , Inibidores de Proteínas Quinases/farmacologia , Quinolinas/farmacologia , Adenosina/química , Adenosina/metabolismo , Animais , Células Cultivadas , Classe I de Fosfatidilinositol 3-Quinases/química , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Cristalografia por Raios X , Modelos Animais de Doenças , Descoberta de Drogas , Feminino , Humanos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Modelos Químicos , Modelos Moleculares , Estrutura Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/metabolismo , Estrutura Terciária de Proteína , Quinolinas/química , Quinolinas/metabolismo , Ratos Endogâmicos Lew , Células Sf9 , Relação Estrutura-AtividadeAssuntos
Doenças Autoimunes/enzimologia , Classe Ia de Fosfatidilinositol 3-Quinase/metabolismo , Classe Ib de Fosfatidilinositol 3-Quinase/metabolismo , Inflamação/enzimologia , Inibidores de Fosfoinositídeo-3 Quinase , Animais , Doenças Autoimunes/tratamento farmacológico , Linfócitos B/enzimologia , Classe Ia de Fosfatidilinositol 3-Quinase/química , Classe Ib de Fosfatidilinositol 3-Quinase/química , Humanos , Inflamação/tratamento farmacológico , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Terapia de Alvo Molecular , Neutrófilos/enzimologia , Conformação Proteica , Linfócitos T/enzimologiaRESUMO
The ICOS (Inducible T cell Co-Stimulator)/B7RP-1 (B7-related protein 1) interaction is critical for the proper activation of a T lymphocyte. In this manuscript we describe a systematic in vivo approach to determine the level of blockade required to impair the generation of a T cell-dependent antibody response. We have developed an overall strategy for correlating drug exposure, target saturation, and efficacy in a biological response that can be generalized for most protein therapeutics. Using this strategy, we determined that low levels of B7RP-1 blockade are still sufficient to inhibit the immune response. These data suggest that contact between the T cell and the antigen-presenting cell during antigen presentation is much more sensitive to inhibition than previously believed and that ICOS/B7RP-1 blockade may be efficacious in the treatment of autoimmune diseases.
Assuntos
Antígeno B7-1/farmacologia , Fenômenos do Sistema Imunitário/efeitos dos fármacos , Hidróxido de Alumínio/imunologia , Animais , Anticorpos Monoclonais/farmacologia , Células Apresentadoras de Antígenos/imunologia , Antígenos CD19/metabolismo , Linfócitos B/metabolismo , Antígeno B7-1/genética , Sítios de Ligação , Complexo CD3/metabolismo , Citocinas/sangue , Relação Dose-Resposta a Droga , Feminino , Fluoresceína-5-Isotiocianato/metabolismo , Corantes Fluorescentes/metabolismo , Hemocianinas/imunologia , Ligante Coestimulador de Linfócitos T Induzíveis , Camundongos , Camundongos Endogâmicos BALB C , Modelos Imunológicos , Ligação Proteica , Proteínas Recombinantes de Fusão/farmacologia , Linfócitos T/metabolismo , Temperatura , Fatores de TempoRESUMO
Autoimmune diseases are marked by the presence of class-switched, high-affinity autoantibodies with pathogenic potential. Costimulation plays an important role in the activation of T cells and the development of T cell-dependent B cell responses. ICOS plays an indispensable role in the development of follicular helper T cells (T(FH) cells), which provide cognate help to germinal center (GC) B cells. We show that the levels of T(FH) cells and GC B cells in two different models of autoimmunity, the New Zealand Black/New Zealand White (NZB/NZW) F(1) mouse model of systemic lupus erythematosus and the collagen-induced arthritis model of rheumatoid arthritis, are dependent on the maintenance of the ICOS/B7RP-1 pathway. Treatment with an anti-B7RP-1 Ab ameliorates disease manifestations and leads to a decrease in T(FH) cells and GC B cells as well as an overall decrease in the frequency of ICOS(+) T cells. Coculture experiments of Ag-primed B cells with CXCR5(+) or CXCR5(-) T cells show that blocking B7RP-1 does not directly impact the production of IgG by B cells. These findings further support the role of ICOS in autoimmunity and suggest that the expansion of the T(FH) cell pool is an important mechanism by which ICOS regulates Ab production.