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Concomitant Detection of Ifna Signature and Activated Monocyte Aricò et al. Journal of Translational Medicine 2011, 9:67 http://www.translational-medicine.com/content/9/1/67 RESEARCH Open Access Concomitant detection of IFNa signature and activated monocyte/dendritic cell precursors in the peripheral blood of IFNa-treated subjects at early times after repeated local cytokine treatments Eleonora Aricò1,2*, Luciano Castiello1,3, Francesca Urbani1, Paola Rizza1, Monica C Panelli2,4, Ena Wang2, Francesco M Marincola2 and Filippo Belardelli1 Abstract Background: Interferons alpha (IFNa) are the cytokines most widely used in clinical medicine for the treatment of cancer and viral infections. Among the immunomodulatory activities possibly involved in their therapeutic efficacy, the importance of IFNa effects on dendritic cells (DC) differentiation and activation has been considered. Despite several studies exploiting microarray technology to characterize IFNa mechanisms of action, there is currently no consensus on the core signature of these cytokines in the peripheral blood of IFNa-treated individuals, as well as on the existence of blood genomic and proteomic markers of low-dose IFNa administered as a vaccine adjuvant. Methods: Gene profiling analysis with microarray was performed on PBMC isolated from melanoma patients and healthy individuals 24 hours after each repeated injection of low-dose IFNa, administered as vaccine adjuvant in two separate clinical trials. At the same time points, cytofluorimetric analysis was performed on CD14+ monocytes, to detect the phenotypic modifications exerted by IFNa on antigen presenting cells precursors. Results: An IFNa signature was consistently observed in both clinical settings 24 hours after each repeated administration of the cytokine. The observed modulation was transient, and did not reach a steady state level refractory to further stimulations. The molecular signature observed ex vivo largely matched the one detected in CD14+ monocytes exposed in vitro to IFNa, including the induction of CXCL10 at the transcriptional and protein level. Interestingly, IFNa ex vivo signature was paralleled by an increase in the percentage and expression of costimulatory molecules by circulating CD14+/CD16+ monocytes, indicated as natural precursors of DC in response to danger signals. Conclusions: Our results provide new insights into the identification of a well defined molecular signature as biomarker of IFNa administered as immune adjuvants, and for the characterization of new molecular and cellular players, such as CXCL10 and CD14+/CD16+ cells, mediating and possibly predicting patient response to these cytokines. * Correspondence: [email protected] 1Department of Cell Biology and Neurosciences Istituto Superiore di Sanità, Rome, Italy Full list of author information is available at the end of the article © 2011 Aricò et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Aricò et al. Journal of Translational Medicine 2011, 9:67 Page 2 of 15 http://www.translational-medicine.com/content/9/1/67 Background insights into candidate predictor biomarkers of response Interferons alpha (IFNa) are still the cytokines most to therapy, and possibly assist in making the appropriate widely used in clinical medicine today, with applications therapeutic decisions when a patient does not present both in oncology and in the treatment of certain viral with a favorable response profile. In spite of many infections [1]. Several decades of research on IFNa have efforts performed in this direction, the literature in this revealed that these cytokines exert immunomodulatory field suffers from a lack of consistency among the activities possibly involved in their in vivo therapeutic results obtained from patients suffering from different efficacy, spanning from the differentiation of the Th1 diseases and receiving different IFNa preparations. The subset, the generation of CTL and the promotion of majority of these studies have been performed in Tcellin vivo proliferation and survival [reviewed in ref. patients chronically infected with HCV, while attempt- [2]]. In particular, IFNa have proved to play an impor- ing to identify a consensus blood biomarker predictive of tant role in the differentiation of monocytes into dendri- IFNa/Ribavirin efficacy in patients blood [9-12,15]. tic cells (DC) and in enhancing DC activities [3-8]. It Since it is known that the pattern of PBMC gene has been suggested that IFNa-mediated DC activation expression in HCV patients is altered by the infection can represent one of the mechanisms underlying the itself [15], IFNa-induced modulations observed in these cytokine therapeutic efficacy in vivo [2]. patients may be somehow related to the HCV disease, In the attempt to understand in more detail the and possible affected by individual-specific variability, mechanisms of IFNa in vivo, several studies have thus providing little information on the general mechan- recently utilized microarray technologies to detect and isms of action of the cytokine per se. analyze an IFNa-specific signature in the peripheral Despite the accumulating information on the IFNa- blood cells of IFNa-treated individuals, with particular induced genes and of their possible in vivo role, little is focus on HCV and melanoma patients [9-15]. These known about the consistency of the IFNa signature in studies have revealed that many interferon-stimulated healthy vs cancer patients. A still elusive area of investi- genes [16] (ISG), previously known to be induced by gation is the kinetics of gene up-regulation in correla- this cytokine in other animal or human in vitro settings, tion with the possible appearance of immune cells can be found up-regulated in the blood of patients trea- elicited by IFNa and playing a primary role in the biolo- ted in vivo with the cytokine. Furthermore, novel and gical responses of IFNa-treated cancer patients. Like- unexpected ISG were added to the list of possible in wise, no information is currently available on the vivo mediators of IFNa immunomodulatory and/or anti- transient and long-term effect of low doses of IFNa tumor activity [9-15]. Defining with acceptable accuracy used with modalities typical of a vaccine adjuvant, as the pool of genes considered to be the signature of IFNa, in spite of their now recognized role as natural IFNa in vivo helps to understand the involvement of links between innate and adaptive immunity [2], have this cytokine in clinical as well as therapeutic settings been extensively and generally used in clinics as typical [17,18]. Notably, an IFNa signature has been observed antiviral or antitumor drugs. As a matter of fact, in systemic lupus erythematosus (SLE) patients, suggest- although the more effective and better tolerated pegy- ing that the overexpression of a specific set of genes can lated IFNa2b is now widely used for the therapy of represent the hallmark of in vivo cell exposure to IFNa, HCV infection [22] and in the adjuvant melanoma set- which is commonly detected in the sera of these ting [23], no study is currently available on the clinical patients [19]. More recently, the presence of a promi- use of this molecule administered as vaccine adjuvant. nent IFNa signature has been reported in patients In the present study, we utilized PBMC derived from experiencing a growing list of autoimmune disorders, melanoma patients and healthy individuals, who had including psoriasis, multiple sclerosis, rheumatoid arthri- been enrolled in two clinical trials with similar treat- tis, dermatomyositis, primary biliary cirrhosis and insu- ment schedule, aimed at assessing the role of IFNa lin-dependent diabetes mellitus [20]. These data, administered as vaccine adjuvant. We exploited microar- together with the autoimmune-like phenomena reported ray technology to evaluate and compare the modulations in melanoma patients responding to IFNa therapy [21], of PBMC global gene expression profiles induced by confirmed the involvement of this cytokine in the deli- IFNa in melanoma and normal donors. The effects of cate balance between immunity and autoimmunity. the administration of different doses of IFNa, as well as Besides helping to gain insight into IFNa mechanisms of repeating the administration of the cytokine in suc- of action in vivo, identifying a clear-cut IFNa signature cessive treatment cycles, were evaluated. The kinetics ex vivo opens the possibility to define patterns of gene and the biological significance of the modulations expression profiles significantly associated with IFNa observed at the transcriptional level were correlated treatment efficacy. In turn, this may also provide with the phenotypic changes observed in circulating Aricò et al. Journal of Translational Medicine 2011, 9:67 Page 3 of 15 http://www.translational-medicine.com/content/9/1/67 CD14+ and CD14+/CD16+ monocytes. The overall The microarray data sets obtained from the two clinical results provide new insights in the identification of spe- trials were analyzed separately. For blood collection, 10 ml cific biomarkers for adjuvant IFNa and in the character- of peripheral blood was collected into BD vacutainer™ ization of new molecular and cellular players mediating CPT™/sodium heparin tube and processed for the separa- the response to this cytokine in patients. tion of mononuclear cells from
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