RESUMO
BACKGROUND: The psoriasis xenograft severe combined immunodeficiency (SCID) mouse model is used in drug discovery to obtain preclinical proof-of-principle of new antipsoriatic drug candidates. Validation of this model by antipsoriatic therapeutic agents in clinical use is important to understand its utility as well as its limitations. The effects of the clinically efficacious antitumour necrosis factor-α biologics have not yet been demonstrated in the psoriasis xenograft SCID mouse model. OBJECTIVES: To investigate the effect of etanercept and to explore the time-dependent changes induced by ciclosporin on psoriatic biomarkers at the gene expression level in the psoriasis xenograft SCID mouse model. METHODS: Xenografted SCID mice were treated either with etanercept and vehicle for 2 weeks or with ciclosporin and vehicle for 2 and 4 weeks, respectively. Treatment-induced changes in the psoriatic grafts were assessed by gene expression analysis and compared with published clinical microarray data. The grafts were further evaluated by histology and immunohistochemistry. RESULTS: Etanercept induced normalization of gene expression, which correlated with a significant reduction in epidermal thickness as well as a decrease in the number of proliferative cells. Anti-inflammatory activity induced by ciclosporin preceded the reduction in epidermal hyperplasia. Comparison of the etanercept- and ciclosporin-induced gene expression signatures with clinical microarray data showed significant correlations. CONCLUSIONS: Efficacy of etanercept and ciclosporin could be translated to the psoriasis xenograft SCID mouse model.
Assuntos
Ciclosporina/farmacologia , Fármacos Dermatológicos/farmacologia , Expressão Gênica/efeitos dos fármacos , Imunoglobulina G/farmacologia , Camundongos SCID , Psoríase/tratamento farmacológico , Animais , Biomarcadores/metabolismo , Quimiocinas/efeitos dos fármacos , Quimiocinas/genética , Citocinas/efeitos dos fármacos , Citocinas/genética , Modelos Animais de Doenças , Regulação para Baixo , Etanercepte , Perfilação da Expressão Gênica , Humanos , Camundongos , Psoríase/genética , Receptores do Fator de Necrose Tumoral , Transplante HeterólogoRESUMO
We recently finemapped a type 1 diabetes (T1D)-linked region on chromosome 21, indicating that one or more T1D-linked genes exist in this region with 33 annotated genes. In the current study, we have taken a novel approach using transcriptional profiling in predicting and prioritizing the most likely candidate genes influencing beta-cell function in this region. Two array-based approaches were used, a rat insulinoma cell line (INS-1alphabeta) overexpressing pancreatic duodenum homeobox 1 (pdx-1) and treated with interleukin 1beta (IL-1beta) as well as human pancreatic islets stimulated with a mixture of cytokines. Several candidate genes with likely functional significance in T1D were identified. Genes showing differential expression in the two approaches were highly similar, supporting the role of these specific gene products in cytokine-induced beta-cell damage. These were genes involved in cytokine signaling, oxidative phosphorylation, defense responses and apoptosis. The analyses, furthermore, revealed several transcription factor binding sites shared by the differentially expressed genes and by genes demonstrating highly similar expression profiles with these genes. Comparable findings in the rat beta-cell line and human islets support the validity of the methods used and support this as a valuable approach for gene mapping and identification of genes with potential functional significance in T1D, within a region of linkage.