RESUMO
Psoriasis is a type I-deviated disease characterized by the presence of interferon (IFN)-gamma and multiple IFN-related inflammatory genes in lesions. Because interleukin (IL)-23 is now recognized to play a role in the recruitment of inflammatory cells in a T helper cell (Th)1-mediated disease, we examined psoriasis skin lesions for production of this newly described cytokine. IL-23 is composed of two subunits: a unique p19 subunit and a p40 subunit shared with IL-12. We found a reliable increase in p19 mRNA by quantitative reverse transcription polymerase chain reaction in lesional skin compared with nonlesional skin (22.3-fold increase; P = 0.001). The p40 subunit, shared by IL-12 and IL-23, increased by 11.6-fold compared with nonlesional skin (P = 0.003), but the IL-12 p35 subunit was not increased in lesional skin. IL-23 was expressed mainly by dermal cells and increased p40 immunoreactivity was visualized in large dermal cells in the lesions. Cell isolation experiments from psoriatic tissue showed strong expression of p19 mRNA in cells expressing monocyte (CD14+ CD11c+ CD83-) and mature dendritic cell (DC) markers (CD14- CD11c+ CD83+), whereas in culture, the mRNAs for p40 and p19 were strongly up-regulated in stimulated monocytes and monocyte-derived DCs, persisting in the latter for much longer periods than IL-12. Our data suggest that IL-23 is playing a more dominant role than IL-12 in psoriasis, a Th1 type of human inflammatory disease.
Assuntos
Regulação da Expressão Gênica/imunologia , Interleucinas/genética , Psoríase/genética , Psoríase/imunologia , Pele/imunologia , Adulto , Citometria de Fluxo , Humanos , Interleucina-12/genética , Interleucina-23 , Subunidade p19 da Interleucina-23 , Isoformas de Proteínas/genética , RNA Mensageiro/genética , Pele/patologia , Transcrição GênicaRESUMO
Microarray-based expression profiling studies in the field of oncology have demonstrated encouraging correlations between tumor transcriptional profiles and eventual patient outcomes. These findings have fueled great interest in the application of transcriptional profiling to samples available from real-time clinical trials, and clinical pharmacogenomic objectives utilizing transcriptional profiling strategies are becoming increasingly incorporated into clinical trial study designs. Over the last few years several retrospective studies based on the profiling of archival tumor tissues suggest that transcriptional analysis of oncology samples may provide general prognosis measures, and in some cases may even predict response to specific therapies. Recently the FDA released a voluntary genomic data guidance meant to assist both regulatory agencies and pharmaceutical companies alike in evaluating the potential benefit of implementing expression profiling studies during the preclinical and clinical phases of drug development. Despite the great promise afforded by this technology, the ultimate benefit of applying transcriptional profiling in prospective clinical trials has yet to be realized because a number of practical impediments to this process exist. The multi-fold purpose of the current review is to highlight the increasing evidence from studies that have identified transcriptional signatures in archived tumors prognostic of patient outcome, to describe some of the drivers for the implementation of transcriptional profiling strategies in real-time drug development, to discuss the use of transcriptional profiling in the context of increasingly complex translational medicine strategies, and to highlight the practical issues and potential approaches involved in the successful application of clinical pharmacogenomic objectives during real-time clinical trials. Strategic implementation of transcriptional profiling in early oncology clinical trials can provide an opportunity to identify predictive markers of clinical response and eventually provide a substantial step forward towards the era of personalized medicine.
Assuntos
Perfilação da Expressão Gênica , Neoplasias , Farmacogenética , Transcrição Gênica , Antineoplásicos/uso terapêutico , Ensaios Clínicos como Assunto , Bases de Dados Genéticas , Desenho de Fármacos , Humanos , Armazenamento e Recuperação da Informação , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/patologia , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico , Taxa de Sobrevida , Tecnologia FarmacêuticaRESUMO
Experimental autoimmune encephalomyelitis (EAE) is an animal model of the human autoimmune disease multiple sclerosis (MS) and is primarily driven by T helper type 1 (Th1) cells. Interleukin (IL)-12 and interferon (IFN)-gamma are important cytokines involved in the differentiation and amplification of Th1 cells, however mice deficient in either IFN-gamma or IL-12 still develop EAE. We have used microarray analysis of EAE-affected CNS tissues in wild-type, IFN-gamma -/- and IL-12 -/- animals to identify genes critical for development of EAE. Over 500 genes were regulated in at least one genotype and over 94 genes were regulated in all three. Of those, 17 were also upregulated in spleen during the disease. We show that a majority of the genes regulated in EAE are also regulated in diseased regions of human MS tissues. The genes in the pool of 94 are more likely to be found regulated in MS patients than the genes regulated in only one or two of the mouse strains suggesting that analyzing gene expression under these multiple genetic conditions may lead to better identification of the genes critical for disease development.