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1.
J Clin Invest ; 124(11): 4867-76, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25271622

RESUMO

Chronic graft-versus-host disease (cGVHD) is a life-threatening impediment to allogeneic hematopoietic stem cell transplantation, and current therapies do not completely prevent and/or treat cGVHD. CD4+ T cells and B cells mediate cGVHD; therefore, targeting these populations may inhibit cGVHD pathogenesis. Ibrutinib is an FDA-approved irreversible inhibitor of Bruton's tyrosine kinase (BTK) and IL-2 inducible T cell kinase (ITK) that targets Th2 cells and B cells and produces durable remissions in B cell malignancies with minimal toxicity. Here, we evaluated whether ibrutinib could reverse established cGVHD in 2 complementary murine models, a model interrogating T cell-driven sclerodermatous cGVHD and an alloantibody-driven multiorgan system cGVHD model that induces bronchiolar obliterans (BO). In the T cell-mediated sclerodermatous cGVHD model, ibrutinib treatment delayed progression, improved survival, and ameliorated clinical and pathological manifestations. In the alloantibody-driven cGVHD model, ibrutinib treatment restored pulmonary function and reduced germinal center reactions and tissue immunoglobulin deposition. Animals lacking BTK and ITK did not develop cGVHD, indicating that these molecules are critical to cGVHD development. Furthermore, ibrutinib treatment reduced activation of T and B cells from patients with active cGVHD. Our data demonstrate that B cells and T cells drive cGVHD and suggest that ibrutinib has potential as a therapeutic agent, warranting consideration for cGVHD clinical trials.


Assuntos
Doença Enxerto-Hospedeiro/tratamento farmacológico , Fatores Imunológicos/farmacologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , Adenina/análogos & derivados , Animais , Intervalo Livre de Doença , Avaliação Pré-Clínica de Medicamentos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Fatores Imunológicos/uso terapêutico , Ativação Linfocitária/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Piperidinas , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico
2.
Exp Biol Med (Maywood) ; 239(10): 1380-9, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24872432

RESUMO

Chronic alcohol consumption results in bone loss through increased bone resorption and decreased bone formation. These effects can be reversed by estradiol (E2) supplementation. Soy diets are suggested to have protective effects on bone loss in men and women, as a result of the presence of soy protein-associated phytoestrogens such as genistein (GEN). In this study, male mice were pair-fed (PF), a control diet, an ethanol (EtOH) diet, or EtOH diet supplemented with 250 mg/kg of GEN for 8 weeks to test if GEN protects against bone loss associated with chronic drinking. Interestingly, alcohol consumption reduced cortical area and thickness and trabecular bone volume in both EtOH and EtOH/GEN groups when compared to the corresponding PF and PF/GEN controls, P < 0.05. However, in the trabecular bone compartment, we observed a significant increase in overall trabecular bone density in the PF/GEN group compared to the PF controls. Bone loss in the EtOH-treated mice was associated with the inhibition of osteoblastogenesis as indicated by decreased alkaline phosphatase staining in ex vivo bone marrow cultures, P < 0.05. GEN supplementation improved osteoblastogenesis in the EtOH/GEN cultures compared to the EtOH group, P < 0.05. Vertebral expression of bone-formation markers, osteocalcin, and runt-related transcription factor 2 (Runx2) was also significantly up-regulated in the PF/GEN and EtOH/GEN groups compared to the PF and EtOH-treated groups. GEN supplementation also increased the expression of receptor activator of nuclear factor κ-B ligand (RANKL) in the PF/GEN, an increase that persisted in the EtOH/GEN-treated animals (P < 0.05), and increased basal hydrogen peroxide production and RANKL mRNA expression in primary bone marrow cultures in vitro, P < 0.05. These findings suggest that GEN supplementation increases the overall bone remodeling and, in the context of chronic alcohol consumption, does not protect against the oxidative stress-associated EtOH-mediated bone resorption.


Assuntos
Reabsorção Óssea/induzido quimicamente , Reabsorção Óssea/prevenção & controle , Suplementos Nutricionais , Etanol/efeitos adversos , Genisteína/administração & dosagem , Fitoestrógenos/administração & dosagem , Animais , Osso e Ossos/patologia , Dieta/métodos , Masculino , Camundongos Endogâmicos C57BL , Resultado do Tratamento
3.
Alcohol Clin Exp Res ; 38(3): 672-82, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24256560

RESUMO

BACKGROUND: In bone, NADPH oxidase (NOX)-derived reactive oxygen species (ROS) superoxide and/or hydrogen peroxide are an important stimulus for osteoclast differentiation and activity. Previously, we have demonstrated that chronic ethanol (EtOH) consumption generates excess NOX-dependent ROS in osteoblasts, which functions to stimulate nuclear factor kappa-ß receptor ligand (RANKL)-RANK signaling, thus increasing osteoclastogenesis and activity. This activity can be blocked by co-administration of EtOH with the pan-NOX inhibitor diphenylene idonium (DPI). METHODS: To test whether EtOH-induced bone loss is dependent on a functional NOX2 enzyme, 6-week-old female C57BL/6J-Ncf1/p47phox(-/-) (p47phox KO) and wild-type (WT) mice were pair-fed EtOH diets for 40 days. Bone loss was assessed by 3-point bending, micro-computed tomography and static histomorphometric analysis. Additionally, ST2 cultured cells were co-treated with EtOH and NOX inhibitors, DPI, gliotoxin, and plumbagin, after which changes in ROS production, and in RANKL and NOX mRNA expression were analyzed. RESULTS: In WT mice, EtOH treatment significantly reduced bone density and mechanical strength, and increased total osteoclast number and activity. In EtOH-treated p47phox KO mice, bone density and mechanical strength were completely preserved. EtOH p47phox KO mice had no changes in osteoclast numbers or activity, and no elevations in serum CTX or RANKL gene expression (p < 0.05). In both WT and p47phox KO mice, EtOH feeding reduced biochemical markers of bone formation (p < 0.05). In vitro EtOH exposure of ST2 cells increased ROS, which was blocked by pretreating with DPI or the NOX2 inhibitor gliotoxin. EtOH-induced RANKL and NOX2 gene expression were inhibited by the NOX4-specific inhibitor plumbagin. CONCLUSIONS: These data suggest that NOX2-derived ROS is necessary for EtOH-induced bone resorption. In osteoblasts, NOX2 and NOX4 appear to work in tandem to increase RANKL expression, whereas EtOH-mediated inhibition of bone formation occurs via a NOX2-independent mechanism.


Assuntos
Reabsorção Óssea/induzido quimicamente , Depressores do Sistema Nervoso Central/efeitos adversos , Etanol/efeitos adversos , Glicoproteínas de Membrana/metabolismo , NADPH Oxidases/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Animais , Reabsorção Óssea/enzimologia , Células Cultivadas , Feminino , Genótipo , Glicoproteínas de Membrana/antagonistas & inibidores , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NADPH Oxidase 2 , NADPH Oxidases/antagonistas & inibidores , NADPH Oxidases/genética , Osteogênese/efeitos dos fármacos , Ligante RANK/metabolismo , Distribuição Aleatória
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