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Interferon-α-Conditioned Human Monocytes Combine a Th1-Orienting Attitude with the Induction of Autologous Th17 Responses: Role of IL-23 and IL-12
Stefano M. Santini,Caterina Lapenta,Simona Donati,Francesca Spadaro,Filippo Belardelli,Maria Ferrantini
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0017364
Abstract: IFN-α exerts multiple effects leading to immune protection against pathogens and cancer as well to autoimmune reactions by acting on monocytes and dendritic cells. We analyzed the versatility of human monocytes conditioned by IFN-α towards dendritic cell differentiation (IFN-DC) in shaping the autologous T-helper response. Priming of na?ve CD4 T cells with autologous IFN-DC in the presence of either SEA or anti-CD3, resulted, in addition to a prominent expansion of CXCR3+ IFN-γ-producing CD4 Th1 cells, in the emergence of two distinct subsets of IL-17-producing CD4 T cells: i) a predominant Th17 population selectively producing IL-17 and expressing CCR6; ii) a minor Th1/Th17 population, producing both IL-17 and IFN-γ. After phagocytosis of apoptotic cells, IFN-DC induced Th17 cell expansion and IL-17 release. Notably, the use of neutralizing antibodies revealed that IL-23 was an essential cytokine in mediating Th17 cell development by IFN-DC. The demonstration of the IFN-DC-induced expansion of both Th1 and Th17 cell populations reveals the intrinsic plasticity of these DC in orienting the immune response and provides a mechanistic link between IFN-α and the onset of autoimmune phenomena, which have been correlated with both IL-17 production and exposure to IFN-α.
The use of microarray technologies in clinical oncology
L Gabriele, F Moretti, MA Pierotti, FM Marincola, R Foà, FM Belardelli
Journal of Translational Medicine , 2006, DOI: 10.1186/1479-5876-4-8
Abstract: Microarray technologies have been extensively used to evaluate genetic markers and changes in gene expression associated with cancer onset and progression for certain types of solid tumors [2]. Ulrich Hengge (Duesseldorf, Germany) discussed his findings on human melanoma: a cancer whose progression from benign to various levels of malignant behavior has been extensively characterized at the histopathological level. Microarray technology identified two potential independent predictors of malignant behavior; activator of S phase kinase (ASK/HuDbf4) and tumor potentiation region (Tpr). Both were significantly over expressed in primary melanomas, subcutaneous melanoma metastases, and metastatic melanoma cell lines (BML, MV3, M13) as opposed to congenital nevi. Moreover, it was found that approximately 86% of the melanoma metastases over expressed ASK/HuDbf4 and Tpr as compared to other markers commonly used for detection of melanoma progression/metastasis such as CD146/MUC18 (13%) and c-Met (53%) [3]. In an attempt to identify genes relevant for human melanoma progression, Marco Paggi (Rome, Italy) provided cDNA array-based evidence of clear-cut RNA over expression of the ferritin light chain (FTL) in the LM metastatic cell line, derived from a supra-clavicular lymph node metastasis. Immunohistochemical analysis validated this finding demonstrating that ferritin is consistently over expressed in paired samples in which autologous lymph node melanoma metastases were compared to primary tumors. Similarly, Bertrand Rihn (Nancy, France) described array-based portraits of normal and cancerous pleura relevant to the understanding of asbestos-mediated carcinogenesis. In three independent studies, overexpression of both FLT and TXN (thioredoxin) was consistently associated with the acquisition of a malignant phenotype.Microarray technology has provided the opportunity to begin a comprehensive molecular and genetic profiling of human breast cancer [4]. Although the estrogen rece
Translational research on advanced therapies
Belardelli,Filippo; Rizza,Paola; Moretti,Franca; Carella,Cintia; Galli,Maria Cristina; Migliaccio,Giovanni;
Annali dell'Istituto Superiore di Sanità , 2011, DOI: 10.4415/ANN_11_01_15
Abstract: fostering translational research of advanced therapies has become a major priority of both scientific community and national governments. advanced therapy medicinal products (atmp) are a new medicinal product category comprising gene therapy and cell-based medicinal products as well as tissue engineered medicinal products. atmp development opens novel avenues for therapeutic approaches in numerous diseases, including cancer and neurodegenerative and cardiovascular diseases. however, there are important bottlenecks for their development due to the complexity of the regulatory framework, the high costs and the needs for good manufacturing practice (gmp) facilities and new end-points for clinical experimentation. thus, a strategic cooperation between different stakeholders (academia, industry and experts in regulatory issues) is strongly needed. recently, a great importance has been given to research infrastructures dedicated to foster translational medicine of advanced therapies. some ongoing european initiatives in this field are presented and their potential impact is discussed.
Concomitant detection of IFNα signature and activated monocyte/dendritic cell precursors in the peripheral blood of IFNα-treated subjects at early times after repeated local cytokine treatments
Eleonora Aricò, Luciano Castiello, Francesca Urbani, Paola Rizza, Monica C Panelli, Ena Wang, Francesco M Marincola, Filippo Belardelli
Journal of Translational Medicine , 2011, DOI: 10.1186/1479-5876-9-67
Abstract: 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 IFNα, 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 IFNα on antigen presenting cells precursors.An IFNα 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 IFNα, including the induction of CXCL10 at the transcriptional and protein level. Interestingly, IFNα 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.Our results provide new insights into the identification of a well defined molecular signature as biomarker of IFNα 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.Interferons alpha (IFNα) are still the cytokines most widely used in clinical medicine today, with applications both in oncology and in the treatment of certain viral infections [1]. Several decades of research on IFNα have revealed that these cytokines exert immunomodulatory activities possibly involved in their in vivo therapeutic efficacy, spanning from the differentiation of the Th1 subset, the generation of CTL and the promotion of T cell in vivo proliferation and survival [reviewed in ref. [2]]. In particular, IFNα have proved to play an important role in the differen
The Italian Network for Tumor Biotherapy (NIBIT): Getting together to push the field forward
Michele Maio, Hugues JM Nicolay, Paolo Ascierto, Filippo Belardelli, Roberto Camerini, Mario P Colombo, Paola Queirolo, Ruggero Ridolfi, Vincenzo Russo, Lucia Anzalone, Ester Fonsatti, Giorgio Parmiani
Journal of Translational Medicine , 2008, DOI: 10.1186/1479-5876-6-8
Abstract: The meeting took place in a monastery built by the Carthusian Order on August 1343, located on the border between the town-states of Florence and Siena. The Certosa of Pontignano preserved through the ages its original atmosphere as an oasis of peace (Fig. 1). Nowadays, the monastery is an University guesthouse where the annual symposium of the NIBIT (acronym for the Network Italiano per la Bioterapia dei Tumori – Italian Network for Tumor Biotherapy) is organized. Tuscan landscape and culinary specialties provided a peace of mind and body that helped to reach the event goals.The increasing knowledge of the molecular mechanisms involved in neoplastic transformation, of the biology of cancer cells, and of the immunological mechanisms regulating tumor-host interactions allows to identify and to apply novel and eventually more effective bio-immunotherapeutic strategies in cancer patients [1].However, for their optimal clinical development, and for their swift translation from the laboratory to the clinical setting, these new therapeutic approaches require a tight cultural and operative interaction among different professionals involved in the clinical, regulatory and industrial fields [2,3]. Thus, a shared effort is mandatory in order to evaluate with due appropriateness, rapidity and scientific rigor the biological and clinical efficacy of novel treatments that become available. Nevertheless, while cancer bio-immunotherapy is consolidating its role as an additional and powerful option in the comprehensive treatment of cancer patients, it raises new and specific procedural, ethical, and legal challenges to its broader clinical application. Therefore, the efficient clinical development and application of new modalities of cancer bio-immunotherapy is often difficult for large research entities and in most cases impossible for small research units [4].On these premises, and to cope with a need strongly felt by the Italian academic, industrial and regulatory community, the
IFN-α Regulates Blimp-1 Expression via miR-23a and miR-125b in Both Monocytes-Derived DC and pDC
Stefania Parlato, Roberto Bruni, Paola Fragapane, Debora Salerno, Cinzia Marcantonio, Paola Borghi, Paola Tataseo, Anna Rita Ciccaglione, Carlo Presutti, Giulia Romagnoli, Irene Bozzoni, Filippo Belardelli, Lucia Gabriele
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0072833
Abstract: Type I interferon (IFN-I) have emerged as crucial mediators of cellular signals controlling DC differentiation and function. Human DC differentiated from monocytes in the presence of IFN-α (IFN-α DC) show a partially mature phenotype and a special capability of stimulating CD4+ T cell and cross-priming CD8+ T cells. Likewise, plasmacytoid DC (pDC) are blood DC highly specialized in the production of IFN-α in response to viruses and other danger signals, whose functional features may be shaped by IFN-I. Here, we investigated the molecular mechanisms stimulated by IFN-α in driving human monocyte-derived DC differentiation and performed parallel studies on peripheral unstimulated and IFN-α-treated pDC. A specific miRNA signature was induced in IFN-α DC and selected miRNAs, among which miR-23a and miR-125b, proved to be negatively associated with up-modulation of Blimp-1 occurring during IFN-α-driven DC differentiation. Of note, monocyte-derived IFN-α DC and in vitro IFN-α-treated pDC shared a restricted pattern of miRNAs regulating Blimp-1 expression as well as some similar phenotypic, molecular and functional hallmarks, supporting the existence of a potential relationship between these DC populations. On the whole, these data uncover a new role of Blimp-1 in human DC differentiation driven by IFN-α and identify Blimp-1 as an IFN-α-mediated key regulator potentially accounting for shared functional features between IFN-α DC and pDC.
Interferon Regulatory Factor 8-Deficiency Determines Massive Neutrophil Recruitment but T Cell Defect in Fast Growing Granulomas during Tuberculosis
Stefano Rocca, Giovanna Schiavoni, Michela Sali, Antonio Giovanni Anfossi, Laura Abalsamo, Ivana Palucci, Fabrizio Mattei, Massimo Sanchez, Anna Giagu, Elisabetta Antuofermo, Giovanni Fadda, Filippo Belardelli, Giovanni Delogu, Lucia Gabriele
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0062751
Abstract: Following Mycobacterium tuberculosis (Mtb) infection, immune cell recruitment in lungs is pivotal in establishing protective immunity through granuloma formation and neogenesis of lymphoid structures (LS). Interferon regulatory factor-8 (IRF-8) plays an important role in host defense against Mtb, although the mechanisms driving anti-mycobacterial immunity remain unclear. In this study, IRF-8 deficient mice (IRF-8?/?) were aerogenously infected with a low-dose Mtb Erdman virulent strain and the course of infection was compared with that induced in wild-type (WT-B6) counterparts. Tuberculosis (TB) progression was examined in both groups using pathological, microbiological and immunological parameters. Following Mtb exposure, the bacterial load in lungs and spleens progressed comparably in the two groups for two weeks, after which IRF-8?/? mice developed a fatal acute TB whereas in WT-B6 the disease reached a chronic stage. In lungs of IRF-8?/?, uncontrolled growth of pulmonary granulomas and impaired development of LS were observed, associated with unbalanced homeostatic chemokines, progressive loss of infiltrating T lymphocytes and massive prevalence of neutrophils at late infection stages. Our data define IRF-8 as an essential factor for the maintenance of proper immune cell recruitment in granulomas and LS required to restrain Mtb infection. Moreover, IRF-8?/? mice, relying on a common human and mouse genetic mutation linked to susceptibility/severity of mycobacterial diseases, represent a valuable model of acute TB for comparative studies with chronically-infected congenic WT-B6 for dissecting protective and pathological immune reactions.
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