46 results on '"Montaldo E"'
Search Results
2. Group 3 innate lymphoid cells regulate neutrophil migration and function in human decidua
- Author
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Croxatto, D., primary, Micheletti, A., additional, Montaldo, E., additional, Orecchia, P., additional, Loiacono, F., additional, Canegallo, F., additional, Calzetti, F., additional, Fulcheri, E., additional, Munari, E., additional, Zamò, A., additional, Venturini, P.L., additional, Moretta, L., additional, Cassatella, M.A., additional, Mingari, M.C., additional, and Vacca, P., additional
- Published
- 2016
- Full Text
- View/download PDF
3. The generation of human innate lymphoid cells is influenced by the source of hematopoietic stem cells and by the use of G-CSF
- Author
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Moretta, F., Petronelli, F., Lucarelli, B., Pitisci, A., Bertaina, A., Locatelli, Franco, Mingari, M. C., Moretta, L., Montaldo, E., Locatelli F. (ORCID:0000-0002-7976-3654), Moretta, F., Petronelli, F., Lucarelli, B., Pitisci, A., Bertaina, A., Locatelli, Franco, Mingari, M. C., Moretta, L., Montaldo, E., and Locatelli F. (ORCID:0000-0002-7976-3654)
- Abstract
NK cells play a central role in the haploidentical HSC transplantation (HSCT) to cure high-risk leukemias. Other innate lymphoid cells (ILCs) have been proposed to exert a protective role in graft-versus-host disease and could also contribute to anti-microbial defence and to lymphoid tissue remodeling. Thus, we investigated the ILC differentiation potential of HSCs isolated from BM, mobilized peripheral blood (PB), and umbilical cord blood (UCB). BM CD34+ cells are enriched in lymphoid-committed precursors, while PB CD34+ cells preferentially contain myeloid precursors. In vitro differentiation experiments revealed that the highest and the lowest CD56+CD161+ ILC recovery was detected in UCB and PB HSC cultures, respectively. Among CD56+CD161+ ILCs, the ratio between NK cells and ILC3s was similar for all HSC analyzed. ILC recovery in PB CD34+ cultures was lower for G-CSF-mobilized HSCs (good mobilizers) than for G-CSF+plerixafor-mobilized HSC (poor mobilizers). Moreover, G-CSF inhibited in vitro ILC recovery and the degree of inhibition was proportional to the time of exposure to the cytokine. Thus, although all common sources of HSC for transplant differentiate towards ILCs, substantial differences exist among different sources and G-CSF may influence ILC recovery. These data offer new clues for a better understanding of the immune reconstitution after HSCT.
- Published
- 2016
4. Human natural killer cells: news in the therapy of solid tumors and high-risk leukemias
- Author
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Pietra, G., Vitale, C., Pende, D., Bertaina, A., Moretta, F., Falco, M., Vacca, P., Montaldo, E., Cantoni, C., Mingari, M. C., Moretta, A., Locatelli, Franco, Moretta, L., Locatelli F. (ORCID:0000-0002-7976-3654), Pietra, G., Vitale, C., Pende, D., Bertaina, A., Moretta, F., Falco, M., Vacca, P., Montaldo, E., Cantoni, C., Mingari, M. C., Moretta, A., Locatelli, Franco, Moretta, L., and Locatelli F. (ORCID:0000-0002-7976-3654)
- Abstract
It is well established that natural killer (NK) cells play an important role in the immunity against cancer, while the involvement of other recently identified, NK-related innate lymphoid cells is still poorly defined. In the haploidentical hematopoietic stem cell transplantation for the therapy of high-risk leukemias, NK cells have been shown to exert a key role in killing leukemic blasts residual after conditioning. While the clinical results in the cure of leukemias are excellent, the exploitation of NK cells in the therapy of solid tumors is still limited and unsatisfactory. In solid tumors, NK cell function may be inhibited via different mechanisms, occurring primarily at the tumor site. The cellular interactions in the tumor microenvironment involve tumor cells, stromal cells and resident or recruited leukocytes and may favor tumor evasion from the host’s defenses. In this context, a number of cytokines, growth factors and enzymes synthesized by tumor cells, stromal cells, suppressive/regulatory myeloid and lymphoid cells may substantially impair the function of different tumor-reactive effector cells, including NK cells. The identification and characterization of such mechanisms may offer clues for the development of new immunotherapeutic strategies to restore effective anti-tumor responses. In order to harness NK cell-based immunotherapies, several approaches have been proposed, including reinforcement of NK cell cytotoxicity by means of specific cytokines, antibodies or drugs. These new tools may improve NK cell function and/or increase tumor susceptibility to NK-mediated killing. Hence, the integration of NK-based immunotherapies with conventional anti-tumor therapies may increase chances of successful cancer treatment.
- Published
- 2016
5. Human innate lymphoid cells
- Author
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Montaldo, E., Vacca, P., Vitale, C., Moretta, F., Locatelli, Franco, Mingari, M. C., Moretta, L., Locatelli F. (ORCID:0000-0002-7976-3654), Montaldo, E., Vacca, P., Vitale, C., Moretta, F., Locatelli, Franco, Mingari, M. C., Moretta, L., and Locatelli F. (ORCID:0000-0002-7976-3654)
- Abstract
The interest in innate lymphoid cells (ILC) has rapidly grown during the last decade. ILC include distinct cell types that are collectively involved in host protection against pathogens and tumor cells and in the regulation of tissue homeostasis. Studies in mice enabled a broad characterization of ILC function and of their developmental requirements. In humans all mature ILC subsets have been characterized and their role in the pathogenesis of certain disease is emerging. Nonetheless, still limited information is available on human ILC development. Indeed, only the cell precursors committed toward NK cells or ILC3 have been described. Here, we review the most recent finding on human mature ILC, discussing their tissue localization and function. Moreover, we summarize the available data regarding human ILC development.
- Published
- 2016
6. CXCL8 production and absence of LFA-1 surface expression identify human NK cells at early stages of differentiation characterized by CD161 molecule with activating function
- Author
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Vitale, C., Montaldo, E., Cottalasso, F., Conte, R., Glatzer, T., Ambrosini, P., Lorenzo Moretta, and Mingari, M. C.
- Published
- 2012
7. Identification of diverse innate lymphoid cells in human decidua
- Author
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Vacca, P., primary, Montaldo, E., additional, Croxatto, D., additional, Loiacono, F., additional, Canegallo, F., additional, Venturini, P.L., additional, Moretta, L., additional, and Mingari, M.C., additional
- Published
- 2015
- Full Text
- View/download PDF
8. IL-1 -releasing human acute myeloid leukemia blasts modulate natural killer cell differentiation from CD34+ precursors
- Author
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Vitale, C., primary, Ambrosini, P., additional, Montaldo, E., additional, Ballerini, F., additional, Moretta, L., additional, and Mingari, M. C., additional
- Published
- 2014
- Full Text
- View/download PDF
9. Agent-based Architectures for Workflow Management in Manufacturing
- Author
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Boccalatte, Antonio, Coccoli, Mauro, Montaldo, E., Paolucci, Massimo, and Sacile, Roberto
- Published
- 2000
10. Applicazione di Agenti Software ai Sistemi Informativi Manifatturieri - Software Agents Applied to Manufacturing Information Systems
- Author
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Bergonzi, S., Boccalatte, Antonio, Coccoli, Mauro, Montaldo, E., Paolucci, Massimo, and Sacile, Roberto
- Published
- 2000
11. Intelligent Agents Applied to Manufacturing: the MAKE-IT Approach
- Author
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Sacile, Roberto, Montaldo, E., Paolucci, Massimo, and Boccalatte, Antonio
- Published
- 2000
12. Internet e Agenti nei Sistemi di Controllo di Processi Industriali. Un’opportunità reale o mera prospettiva tecnologica? – Internet and Agent Technology in the Control Systems of Industrial Processes. A real opportunity or a mere technology perspective?
- Author
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Boccalatte, Antonio, Coccoli, Mauro, Montaldo, E., Paolucci, Massimo, and Sacile, Roberto
- Published
- 2000
13. Intelligent Agents Applied to Workflow Management in Manufacturing Information Systems
- Author
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Sacile, Roberto, Montaldo, E., Paolucci, Massimo, and Boccalatte, Antonio
- Published
- 2000
14. Lymphocyte and markers of inflammation detection in the conjunctival epithelium of patients with dry eye by enhanced flow cytometry
- Author
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BARABINO, S, primary, MONTALDO, E, additional, SOLIGNANI, F, additional, MINGARI, C, additional, and ROLANDO, M, additional
- Published
- 2009
- Full Text
- View/download PDF
15. Methylprednisolone induces preferential and rapid differentiation of CD34+ cord blood precursors toward NK cells
- Author
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Vitale, C., primary, Cottalasso, F., additional, Montaldo, E., additional, Moretta, L., additional, and Mingari, M. C., additional
- Published
- 2008
- Full Text
- View/download PDF
16. A decision support system to detect morphologic changes of chromatin arrangement in normal-appearing cells
- Author
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Sacile, R., primary, Montaldo, E., additional, Ruggiero, C., additional, Nieburgs, H.E., additional, and Nicolo, G., additional
- Published
- 2003
- Full Text
- View/download PDF
17. Immune signature drives leukemia escape and relapse after hematopoietic cell transplantation
- Author
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Leo Luznik, Luca Vago, Dietrich W. Beelen, Elisa Montaldo, Matteo Barcella, Robert Zeiser, Bernhard Gentner, Gabriele Bucci, Raynier Devillier, Renato Ostuni, Matteo Carrabba, Masahiro Onozawa, Valentina Gambacorta, Orietta Spinelli, Miguel Waterhouse, Katharina Fleischhauer, Elia Stupka, Ivana Gojo, Chiara Bonini, Cristina Toffalori, Lara Crucitti, Laura Zito, Raffaella Greco, Michela Riba, Matteo Maria Naldini, Dejan Lazarevic, Massimo Bernardi, Maddalena Noviello, Davide Cittaro, Takanori Teshima, Didier Blaise, Jacopo Peccatori, Cristina Barlassina, Francesco Manfredi, Giovanni Tonon, Giacomo Oliveira, Alessandro Rambaldi, Constantijn J.M. Halkes, Marieke Griffioen, Maher Hanoun, Nicoletta Cieri, Fabio Ciceri, Jürgen Finke, Toffalori, C., Zito, L., Gambacorta, V., Riba, M., Oliveira, G., Bucci, G., Barcella, M., Spinelli, O., Greco, R., Crucitti, L., Cieri, N., Noviello, M., Manfredi, F., Montaldo, E., Ostuni, R., Naldini, M. M., Gentner, B., Waterhouse, M., Zeiser, R., Finke, J., Hanoun, M., Beelen, D. W., Gojo, I., Luznik, L., Onozawa, M., Teshima, T., Devillier, R., Blaise, D., Halkes, C. J. M., Griffioen, M., Carrabba, M. G., Bernardi, M., Peccatori, J., Barlassina, C., Stupka, E., Lazarevic, D., Tonon, G., Rambaldi, A., Cittaro, D., Bonini, C., Fleischhauer, K., Ciceri, F., Vago, L., Toffalori, C, Zito, L, Gambacorta, V, Riba, M, Oliveira, G, Bucci, G, Barcella, M, Spinelli, O, Greco, R, Crucitti, L, Cieri, N, Noviello, M, Manfredi, F, Montaldo, E, Ostuni, R, Naldini, M, Gentner, B, Waterhouse, M, Zeiser, R, Finke, J, Hanoun, M, Beelen, D, Gojo, I, Luznik, L, Onozawa, M, Teshima, T, Devillier, R, Blaise, D, Halkes, C, Griffioen, M, Carrabba, M, Bernardi, M, Peccatori, J, Barlassina, C, Stupka, E, Lazarevic, D, Tonon, G, Rambaldi, A, Cittaro, D, Bonini, C, Fleischhauer, K, Ciceri, F, and Vago, L
- Subjects
0301 basic medicine ,Myeloid ,medicine.medical_treatment ,Antigen presentation ,Medizin ,Reproducibility of Result ,Hematopoietic stem cell transplantation ,Lymphocyte Activation ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,0302 clinical medicine ,Recurrence ,hemic and lymphatic diseases ,medicine ,Humans ,Transplantation, Homologous ,RNA, Messenger ,Transplantation, Homologou ,business.industry ,Gene Expression Regulation, Leukemic ,Gene Expression Profiling ,Histocompatibility Antigens Class II ,Hematopoietic Stem Cell Transplantation ,Reproducibility of Results ,Myeloid leukemia ,General Medicine ,medicine.disease ,Transplantation ,Haematopoiesis ,Leukemia ,Leukemia, Myeloid, Acute ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Cancer research ,business ,CD80 ,Human - Abstract
Transplantation of hematopoietic cells from a healthy individual (allogeneic hematopoietic cell transplantation (allo-HCT)) demonstrates that adoptive immunotherapy can cure blood cancers: still, post-transplantation relapses remain frequent. To explain their drivers, we analyzed the genomic and gene expression profiles of acute myeloid leukemia (AML) blasts purified from patients at serial time-points during their disease history. We identified a transcriptional signature specific for post-transplantation relapses and highly enriched in immune-related processes, including T cell costimulation and antigen presentation. In two independent patient cohorts we confirmed the deregulation of multiple costimulatory ligands on AML blasts at post-transplantation relapse (PD-L1, B7-H3, CD80, PVRL2), mirrored by concomitant changes in circulating donor T cells. Likewise, we documented the frequent loss of surface expression of HLA-DR, -DQ and -DP on leukemia cells, due to downregulation of the HLA class II regulator CIITA. We show that loss of HLA class II expression and upregulation of inhibitory checkpoint molecules represent alternative modalities to abolish AML recognition from donor-derived T cells, and can be counteracted by interferon-gamma or checkpoint blockade, respectively. Our results demonstrate that the deregulation of pathways involved in T cell-mediated allorecognition is a distinctive feature and driver of AML relapses after allo-HCT, which can be rapidly translated into personalized therapies.
- Published
- 2019
18. A PGE2-MEF2A axis enables context-dependent control of inflammatory gene expression
- Author
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Dario Iodice, Simona Barresi, Marco Genua, Pietro Di Lucia, Matteo Iannacone, Dejan Lazarevic, Francesco Maria Vittoria, Elisa Montaldo, Renato Ostuni, Daniela Maria Cirillo, Francesco Cilenti, Giulia Barbiera, Luca Mezzanzanica, Vincenzo Cuzzola, Eleonora Lusito, Paolo Miotto, Nicoletta Caronni, Cilenti, F., Barbiera, G., Caronni, N., Iodice, D., Montaldo, E., Barresi, S., Lusito, E., Cuzzola, V., Vittoria, F. M., Mezzanzanica, L., Miotto, P., Di Lucia, P., Lazarevic, D., Cirillo, D. M., Iannacone, M., Genua, M., and Ostuni, R.
- Subjects
0301 basic medicine ,Mef2 ,Lipopolysaccharides ,LPS ,Lipopolysaccharide ,Immunology ,Inflammation ,Biology ,Dinoprostone ,Cell Line ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Interferon ,medicine ,Immunology and Allergy ,Animals ,Humans ,Enhancer ,Transcription factor ,innate immunity ,Cells, Cultured ,Mitogen-Activated Protein Kinase 7 ,Mice, Knockout ,Innate immune system ,MEF2 Transcription Factors ,Macrophages ,Macrophage Activation ,cytokines ,Chromatin ,Cell biology ,interferons ,Mice, Inbred C57BL ,030104 developmental biology ,Infectious Diseases ,chemistry ,Gene Expression Regulation ,030220 oncology & carcinogenesis ,Interferon Type I ,chromatin ,PGE2 ,medicine.symptom ,MEF2 ,transcription ,medicine.drug - Abstract
Tight control of inflammatory gene expression by antagonistic environmental cues is key to ensure immune protection while preventing tissue damage. Prostaglandin E2 (PGE2) modulates macrophage activation during homeostasis and disease, but the underlying mechanisms remain incompletely characterized. Here we dissected the genomic properties of lipopolysaccharide (LPS)-induced genes whose expression is antagonized by PGE2. The latter molecule targeted a set of inflammatory gene enhancers that, already in unstimulated macrophages, displayed poorly permissive chromatin organization and were marked by the transcription factor myocyte enhancer factor 2A (MEF2A). Deletion of MEF2A phenocopied PGE2 treatment and abolished type I interferon (IFN I) induction upon exposure to innate immune stimuli. Mechanistically, PGE2 interfered with LPS-mediated activation of ERK5, a known transcriptional partner of MEF2. This study highlights principles of plasticity and adaptation in cells exposed to a complex environment and uncovers a transcriptional circuit for IFN I induction with relevance for infectious diseases or cancer.
- Published
- 2021
19. Reduced frequency of infectious complications in patients treated with thymostimulin added to combination chemotherapy in primitive lung cancer
- Author
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Del Giacco, G.S., Puxeddu, G., Piludu, G., Montaldo, E., Mantovani, G., LoPresti, M., and Pisano, M.
- Published
- 1985
- Full Text
- View/download PDF
20. IL-1β + macrophages fuel pathogenic inflammation in pancreatic cancer.
- Author
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Caronni N, La Terza F, Vittoria FM, Barbiera G, Mezzanzanica L, Cuzzola V, Barresi S, Pellegatta M, Canevazzi P, Dunsmore G, Leonardi C, Montaldo E, Lusito E, Dugnani E, Citro A, Ng MSF, Schiavo Lena M, Drago D, Andolfo A, Brugiapaglia S, Scagliotti A, Mortellaro A, Corbo V, Liu Z, Mondino A, Dellabona P, Piemonti L, Taveggia C, Doglioni C, Cappello P, Novelli F, Iannacone M, Ng LG, Ginhoux F, Crippa S, Falconi M, Bonini C, Naldini L, Genua M, and Ostuni R
- Subjects
- Humans, Carcinogenesis, Carcinoma, Pancreatic Ductal complications, Carcinoma, Pancreatic Ductal immunology, Carcinoma, Pancreatic Ductal pathology, Dinoprostone metabolism, Disease Progression, Gene Expression Regulation, Neoplastic, Tumor Microenvironment, Tumor Necrosis Factors metabolism, Inflammation complications, Inflammation immunology, Inflammation pathology, Interleukin-1beta immunology, Interleukin-1beta metabolism, Pancreatic Neoplasms complications, Pancreatic Neoplasms immunology, Pancreatic Neoplasms pathology, Tumor-Associated Macrophages immunology, Tumor-Associated Macrophages metabolism, Tumor-Associated Macrophages pathology
- Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with high resistance to therapies
1 . Inflammatory and immunomodulatory signals co-exist in the pancreatic tumour microenvironment, leading to dysregulated repair and cytotoxic responses. Tumour-associated macrophages (TAMs) have key roles in PDAC2 , but their diversity has prevented therapeutic exploitation. Here we combined single-cell and spatial genomics with functional experiments to unravel macrophage functions in pancreatic cancer. We uncovered an inflammatory loop between tumour cells and interleukin-1β (IL-1β)-expressing TAMs, a subset of macrophages elicited by a local synergy between prostaglandin E2 (PGE2 ) and tumour necrosis factor (TNF). Physical proximity with IL-1β+ TAMs was associated with inflammatory reprogramming and acquisition of pathogenic properties by a subset of PDAC cells. This occurrence was an early event in pancreatic tumorigenesis and led to persistent transcriptional changes associated with disease progression and poor outcomes for patients. Blocking PGE2 or IL-1β activity elicited TAM reprogramming and antagonized tumour cell-intrinsic and -extrinsic inflammation, leading to PDAC control in vivo. Targeting the PGE2 -IL-1β axis may enable preventive or therapeutic strategies for reprogramming of immune dynamics in pancreatic cancer., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2023
- Full Text
- View/download PDF
21. Scalable GMP-compliant gene correction of CD4+ T cells with IDLV template functionally validated in vitro and in vivo .
- Author
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Asperti C, Canarutto D, Porcellini S, Sanvito F, Cecere F, Vavassori V, Ferrari S, Rovelli E, Albano L, Jacob A, Sergi Sergi L, Montaldo E, Ferrua F, González-Granado LI, Lougaris V, Badolato R, Finocchi A, Villa A, Radrizzani M, and Naldini L
- Abstract
Hyper-IgM1 is a rare X-linked combined immunodeficiency caused by mutations in the CD40 ligand ( CD40LG ) gene with a median survival of 25 years, potentially treatable with in situ CD4+ T cell gene editing with Cas9 and a one-size-fits-most corrective donor template. Here, starting from our research-grade editing protocol, we pursued the development of a good manufacturing practice (GMP)-compliant, scalable process that allows for correction, selection and expansion of edited cells, using an integrase defective lentiviral vector as donor template. After systematic optimization of reagents and conditions we proved maintenance of stem and central memory phenotypes and expression and function of CD40LG in edited healthy donor and patient cells recapitulating the physiological CD40LG regulation. We then documented the preserved fitness of edited cells by xenotransplantation into immunodeficient mice. Finally, we transitioned to large-scale manufacturing, and developed a panel of quality control assays. Overall, our GMP-compliant process takes long-range gene editing one step closer to clinical application with a reassuring safety profile., Competing Interests: L.N., C.A., M.R., V.V., A.V., S.F., S.P., D.C., and A.J. are inventors of patent applications owned by Ospedale San Raffaele S.r.l. and Fondazione Telethon ETS, including one patent application on CD40LG gene editing. L.N. is founder, quota holder, and consultant of GeneSpire S.r.l., (© 2023 The Authors.)
- Published
- 2023
- Full Text
- View/download PDF
22. Cellular and transcriptional dynamics of human neutrophils at steady state and upon stress.
- Author
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Montaldo E, Lusito E, Bianchessi V, Caronni N, Scala S, Basso-Ricci L, Cantaffa C, Masserdotti A, Barilaro M, Barresi S, Genua M, Vittoria FM, Barbiera G, Lazarevic D, Messina C, Xue E, Marktel S, Tresoldi C, Milani R, Ronchi P, Gattillo S, Santoleri L, Di Micco R, Ditadi A, Belfiori G, Aleotti F, Naldini MM, Gentner B, Gardiman E, Tamassia N, Cassatella MA, Hidalgo A, Kwok I, Ng LG, Crippa S, Falconi M, Pettinella F, Scapini P, Naldini L, Ciceri F, Aiuti A, and Ostuni R
- Subjects
- Biomarkers metabolism, Humans, Interferons genetics, Interferons metabolism, Plastics metabolism, Myelopoiesis, Neutrophils metabolism
- Abstract
Traditionally viewed as poorly plastic, neutrophils are now recognized as functionally diverse; however, the extent and determinants of neutrophil heterogeneity in humans remain unclear. We performed a comprehensive immunophenotypic and transcriptome analysis, at a bulk and single-cell level, of neutrophils from healthy donors and patients undergoing stress myelopoiesis upon exposure to growth factors, transplantation of hematopoietic stem cells (HSC-T), development of pancreatic cancer and viral infection. We uncover an extreme diversity of human neutrophils in vivo, reflecting the rates of cell mobilization, differentiation and exposure to environmental signals. Integrated control of developmental and inducible transcriptional programs linked flexible granulopoietic outputs with elicitation of stimulus-specific functional responses. In this context, we detected an acute interferon (IFN) response in the blood of patients receiving HSC-T that was mirrored by marked upregulation of IFN-stimulated genes in neutrophils but not in monocytes. Systematic characterization of human neutrophil plasticity may uncover clinically relevant biomarkers and support the development of diagnostic and therapeutic tools., (© 2022. Springer Nature America, Inc.)
- Published
- 2022
- Full Text
- View/download PDF
23. Is there a role for tapered topical dose steroidal treatment for dry eye disease? A randomized, pilot study.
- Author
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Barabino S, Montaldo E, Mingari MC, Mazzotta C, Giuffrida S, and Rolando M
- Subjects
- HLA-DR Antigens genetics, Humans, Inflammation, Ophthalmic Solutions therapeutic use, Pilot Projects, Dry Eye Syndromes diagnosis, Dry Eye Syndromes drug therapy, Loteprednol Etabonate therapeutic use
- Abstract
Purpose: To evaluate the effect of tapered doses of loteprednol-etabonate in dry eye disease patients., Materials and Methods: Dry eye and treatment outcomes were assessed by Schirmer I test, tear BUT, lissamine green conjunctival staining, fluorescein corneal staining, and HLA-DR expression on conjunctival cells. Patients received either loteprednol-etabonate 0.5% twice daily for 14 days tapered to once daily for 14 days, and then twice weekly for 28 days ( n = 10), or NaCl 0.9%., Results: A significant decrease of ocular surface inflammation and improvement of symptoms was recorded in the study group compared with controls at days 14 and 56. Change from baseline in HLA-DR expression in CD45+ conjunctival cells was significantly higher in treated patients at day 14. Intraocular pressure and best corrected visual acuity were preserved in all treated eyes., Conclusions: Tapered doses of loteprednol etabonate 0.5% suspension controlled ocular surface inflammation, improving dry eye symptoms.
- Published
- 2022
- Full Text
- View/download PDF
24. A PGE 2 -MEF2A axis enables context-dependent control of inflammatory gene expression.
- Author
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Cilenti F, Barbiera G, Caronni N, Iodice D, Montaldo E, Barresi S, Lusito E, Cuzzola V, Vittoria FM, Mezzanzanica L, Miotto P, Di Lucia P, Lazarevic D, Cirillo DM, Iannacone M, Genua M, and Ostuni R
- Subjects
- Animals, Cell Line, Cells, Cultured, Gene Expression Regulation immunology, Humans, Inflammation genetics, Inflammation immunology, Interferon Type I biosynthesis, Lipopolysaccharides, MEF2 Transcription Factors genetics, MEF2 Transcription Factors immunology, Mice, Mice, Inbred C57BL, Mice, Knockout, Mitogen-Activated Protein Kinase 7 metabolism, Dinoprostone immunology, Interferon Type I immunology, Macrophage Activation immunology, Macrophages immunology
- Abstract
Tight control of inflammatory gene expression by antagonistic environmental cues is key to ensure immune protection while preventing tissue damage. Prostaglandin E
2 (PGE2 ) modulates macrophage activation during homeostasis and disease, but the underlying mechanisms remain incompletely characterized. Here we dissected the genomic properties of lipopolysaccharide (LPS)-induced genes whose expression is antagonized by PGE2 . The latter molecule targeted a set of inflammatory gene enhancers that, already in unstimulated macrophages, displayed poorly permissive chromatin organization and were marked by the transcription factor myocyte enhancer factor 2A (MEF2A). Deletion of MEF2A phenocopied PGE2 treatment and abolished type I interferon (IFN I) induction upon exposure to innate immune stimuli. Mechanistically, PGE2 interfered with LPS-mediated activation of ERK5, a known transcriptional partner of MEF2. This study highlights principles of plasticity and adaptation in cells exposed to a complex environment and uncovers a transcriptional circuit for IFN I induction with relevance for infectious diseases or cancer., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2021
- Full Text
- View/download PDF
25. Determinants, mechanisms, and functional outcomes of myeloid cell diversity in cancer.
- Author
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Caronni N, Montaldo E, Mezzanzanica L, Cilenti F, Genua M, and Ostuni R
- Subjects
- Carcinogenesis, Humans, Myeloid Cells, Neutrophils, Neoplasms therapy, Tumor Microenvironment
- Abstract
Most, if not all, aspects of carcinogenesis are influenced by the tumor microenvironment (TME), a complex architecture of cells, matrix components, soluble signals, and their dynamic interactions in the context of physical traits of the tissue. Expanding application of technologies for high-dimensional analyses with single-cell resolution has begun to decipher the contributions of the immune system to cancer progression and its implications for therapy. In this review, we will discuss the multifaceted roles of tumor-associated macrophages and neutrophils, focusing on factors that subvert tissue immune homeostasis and offer therapeutic opportunities for TME reprogramming. By performing a critical analysis of available datasets, we elaborate on diversification mechanisms and unifying principles of myeloid cell heterogeneity in human tumors., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2021
- Full Text
- View/download PDF
26. Immune signature drives leukemia escape and relapse after hematopoietic cell transplantation.
- Author
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Toffalori C, Zito L, Gambacorta V, Riba M, Oliveira G, Bucci G, Barcella M, Spinelli O, Greco R, Crucitti L, Cieri N, Noviello M, Manfredi F, Montaldo E, Ostuni R, Naldini MM, Gentner B, Waterhouse M, Zeiser R, Finke J, Hanoun M, Beelen DW, Gojo I, Luznik L, Onozawa M, Teshima T, Devillier R, Blaise D, Halkes CJM, Griffioen M, Carrabba MG, Bernardi M, Peccatori J, Barlassina C, Stupka E, Lazarevic D, Tonon G, Rambaldi A, Cittaro D, Bonini C, Fleischhauer K, Ciceri F, and Vago L
- Subjects
- Gene Expression Regulation, Leukemic, Histocompatibility Antigens Class II genetics, Histocompatibility Antigens Class II metabolism, Humans, Leukemia, Myeloid, Acute therapy, Lymphocyte Activation immunology, RNA, Messenger genetics, RNA, Messenger metabolism, Recurrence, Reproducibility of Results, Transplantation, Homologous, Gene Expression Profiling, Hematopoietic Stem Cell Transplantation, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute immunology
- Abstract
Transplantation of hematopoietic cells from a healthy individual (allogeneic hematopoietic cell transplantation (allo-HCT)) demonstrates that adoptive immunotherapy can cure blood cancers: still, post-transplantation relapses remain frequent. To explain their drivers, we analyzed the genomic and gene expression profiles of acute myeloid leukemia (AML) blasts purified from patients at serial time-points during their disease history. We identified a transcriptional signature specific for post-transplantation relapses and highly enriched in immune-related processes, including T cell costimulation and antigen presentation. In two independent patient cohorts we confirmed the deregulation of multiple costimulatory ligands on AML blasts at post-transplantation relapse (PD-L1, B7-H3, CD80, PVRL2), mirrored by concomitant changes in circulating donor T cells. Likewise, we documented the frequent loss of surface expression of HLA-DR, -DQ and -DP on leukemia cells, due to downregulation of the HLA class II regulator CIITA. We show that loss of HLA class II expression and upregulation of inhibitory checkpoint molecules represent alternative modalities to abolish AML recognition from donor-derived T cells, and can be counteracted by interferon-γ or checkpoint blockade, respectively. Our results demonstrate that the deregulation of pathways involved in T cell-mediated allorecognition is a distinctive feature and driver of AML relapses after allo-HCT, which can be rapidly translated into personalized therapies.
- Published
- 2019
- Full Text
- View/download PDF
27. Effect of Tyrosin Kinase Inhibitors on NK Cell and ILC3 Development and Function.
- Author
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Damele L, Montaldo E, Moretta L, Vitale C, and Mingari MC
- Subjects
- CD56 Antigen metabolism, Cell Differentiation, Cells, Cultured, Cytotoxicity, Immunologic, Dasatinib pharmacology, Dasatinib therapeutic use, Drug Resistance, Neoplasm, Hematopoietic Stem Cells physiology, Humans, Imatinib Mesylate pharmacology, Imatinib Mesylate therapeutic use, Interleukins metabolism, Pyrimidines pharmacology, Pyrimidines therapeutic use, Receptors, IgG metabolism, STAT5 Transcription Factor metabolism, Signal Transduction, Interleukin-22, Antineoplastic Agents therapeutic use, Killer Cells, Natural immunology, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Lymphocytes physiology, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Protein Kinase Inhibitors therapeutic use
- Abstract
Tyrosin kinase inhibitors (TKI) sharply improved the prognosis of Chronic Myeloid Leukemia (CML) and of Philadelphia
+ Acute Lymphoblastic Leukemia (Ph+ ALL) patients. However, TKI are not curative because of the development of resistance and lack of complete molecular remission in the majority of patients. Clinical evidences would support the notion that patient's immune system may play a key role in preventing relapses. In particular, increased proportions of terminally differentiated CD56+ CD16+ CD57+ NK cells have been reported to be associated with successful Imatinib therapy discontinuation or with a deep molecular response in Dasatinib-treated patients. In view of the potential role of NK cells in immune-response against CML, it is important to study whether any TKI have an effect on the NK cell development and identify possible molecular mechanism(s) by which continuous exposure to in vitro TKI may influence NK cell development and repertoire. To this end, CD34+ hematopoietic stem cells (HSC) were cultured in the absence or in the presence of Imatinib, Nilotinib, or Dasatinib. We show that all compounds exert an inhibitory effect on CD56+ cell recovery. In addition, Dasatinib sharply skewed the repertoire of CD56+ cell population, leading to an impaired recovery of CD56+ CD117- CD16+ CD94/NKG2A+ EOMES+ mature cytotoxic NK cells, while the recovery of CD56+ CD117+ CD94/NKG2A- RORγt+ IL-22-producing ILC3 was not affected. This effect appears to involve the Dasatinib-mediated inhibition of Src kinases and, indirectly, of STAT5-signaling activation in CD34+ cells during first days of culture. Our studies, reveal a possible mechanism by which Dasatinib may interfere with the proliferation and maturation of fully competent NK cells, i.e., by targeting signaling pathways required for differentiation and survival of NK cells but not of ILC3.- Published
- 2018
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28. Human innate lymphoid cells.
- Author
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Montaldo E, Vacca P, Vitale C, Moretta F, Locatelli F, Mingari MC, and Moretta L
- Subjects
- Animals, Biomarkers, Cell Differentiation immunology, Hematopoietic Stem Cell Transplantation, Humans, Immune System cytology, Immune System immunology, Immune System metabolism, Killer Cells, Natural cytology, Killer Cells, Natural immunology, Killer Cells, Natural metabolism, Lymphocyte Subsets cytology, Organ Specificity, Phenotype, Precursor Cells, T-Lymphoid cytology, Precursor Cells, T-Lymphoid immunology, Precursor Cells, T-Lymphoid metabolism, Signal Transduction, Immunity, Innate, Lymphocyte Subsets immunology, Lymphocyte Subsets metabolism
- Abstract
The interest in innate lymphoid cells (ILC) has rapidly grown during the last decade. ILC include distinct cell types that are collectively involved in host protection against pathogens and tumor cells and in the regulation of tissue homeostasis. Studies in mice enabled a broad characterization of ILC function and of their developmental requirements. In humans all mature ILC subsets have been characterized and their role in the pathogenesis of certain disease is emerging. Nonetheless, still limited information is available on human ILC development. Indeed, only the cell precursors committed toward NK cells or ILC3 have been described. Here, we review the most recent finding on human mature ILC, discussing their tissue localization and function. Moreover, we summarize the available data regarding human ILC development., (Copyright © 2016 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.)
- Published
- 2016
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29. NK Cells and Other Innate Lymphoid Cells in Hematopoietic Stem Cell Transplantation.
- Author
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Vacca P, Montaldo E, Croxatto D, Moretta F, Bertaina A, Vitale C, Locatelli F, Mingari MC, and Moretta L
- Abstract
Natural killer (NK) cells play a major role in the T-cell depleted haploidentical hematopoietic stem cell transplantation (haplo-HSCT) to cure high-risk leukemias. NK cells belong to the expanding family of innate lymphoid cells (ILCs). At variance with NK cells, the other ILC populations (ILC1/2/3) are non-cytolytic, while they secrete different patterns of cytokines. ILCs provide host defenses against viruses, bacteria, and parasites, drive lymphoid organogenesis, and contribute to tissue remodeling. In haplo-HSCT patients, the extensive T-cell depletion is required to prevent graft-versus-host disease (GvHD) but increases risks of developing a wide range of life-threatening infections. However, these patients may rely on innate defenses that are reconstituted more rapidly than the adaptive ones. In this context, ILCs may represent important players in the early phases following transplantation. They may contribute to tissue homeostasis/remodeling and lymphoid tissue reconstitution. While the reconstitution of NK cell repertoire and its role in haplo-HSCT have been largely investigated, little information is available on ILCs. Of note, CD34(+) cells isolated from different sources of HSC may differentiate in vitro toward various ILC subsets. Moreover, cytokines released from leukemia blasts (e.g., IL-1β) may alter the proportions of NK cells and ILC3, suggesting the possibility that leukemia may skew the ILC repertoire. Further studies are required to define the timing of ILC development and their potential protective role after HSCT.
- Published
- 2016
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30. The generation of human innate lymphoid cells is influenced by the source of hematopoietic stem cells and by the use of G-CSF.
- Author
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Moretta F, Petronelli F, Lucarelli B, Pitisci A, Bertaina A, Locatelli F, Mingari MC, Moretta L, and Montaldo E
- Subjects
- Antigens, CD34 immunology, Benzylamines, Bone Marrow Cells drug effects, Bone Marrow Cells immunology, CD56 Antigen immunology, Cell Count, Cyclams, Fetal Blood physiology, Graft vs Host Disease, Granulocyte Colony-Stimulating Factor pharmacology, Hematopoietic Stem Cells immunology, Heterocyclic Compounds pharmacology, Humans, Lymphocytes immunology, NK Cell Lectin-Like Receptor Subfamily B immunology, Phenotype, Bone Marrow Cells physiology, Fetal Blood cytology, Granulocyte Colony-Stimulating Factor immunology, Hematopoietic Stem Cells physiology, Immunity, Innate, Lymphocytes physiology, Lymphopoiesis
- Abstract
NK cells play a central role in the haploidentical HSC transplantation (HSCT) to cure high-risk leukemias. Other innate lymphoid cells (ILCs) have been proposed to exert a protective role in graft-versus-host disease and could also contribute to anti-microbial defence and to lymphoid tissue remodeling. Thus, we investigated the ILC differentiation potential of HSCs isolated from BM, mobilized peripheral blood (PB), and umbilical cord blood (UCB). BM CD34(+) cells are enriched in lymphoid-committed precursors, while PB CD34(+) cells preferentially contain myeloid precursors. In vitro differentiation experiments revealed that the highest and the lowest CD56(+) CD161(+) ILC recovery was detected in UCB and PB HSC cultures, respectively. Among CD56(+) CD161(+) ILCs, the ratio between NK cells and ILC3s was similar for all HSC analyzed. ILC recovery in PB CD34(+) cultures was lower for G-CSF-mobilized HSCs (good mobilizers) than for G-CSF+plerixafor-mobilized HSC (poor mobilizers). Moreover, G-CSF inhibited in vitro ILC recovery and the degree of inhibition was proportional to the time of exposure to the cytokine. Thus, although all common sources of HSC for transplant differentiate towards ILCs, substantial differences exist among different sources and G-CSF may influence ILC recovery. These data offer new clues for a better understanding of the immune reconstitution after HSCT., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2016
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31. Human natural killer cells: news in the therapy of solid tumors and high-risk leukemias.
- Author
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Pietra G, Vitale C, Pende D, Bertaina A, Moretta F, Falco M, Vacca P, Montaldo E, Cantoni C, Mingari MC, Moretta A, Locatelli F, and Moretta L
- Subjects
- Cell Communication immunology, Cytotoxicity, Immunologic immunology, Humans, Killer Cells, Natural immunology, Leukemia immunology, Models, Immunological, Neoplasms immunology, Tumor Microenvironment immunology, Hematopoietic Stem Cell Transplantation methods, Immunotherapy, Adoptive methods, Killer Cells, Natural transplantation, Leukemia therapy, Neoplasms therapy
- Abstract
It is well established that natural killer (NK) cells play an important role in the immunity against cancer, while the involvement of other recently identified, NK-related innate lymphoid cells is still poorly defined. In the haploidentical hematopoietic stem cell transplantation for the therapy of high-risk leukemias, NK cells have been shown to exert a key role in killing leukemic blasts residual after conditioning. While the clinical results in the cure of leukemias are excellent, the exploitation of NK cells in the therapy of solid tumors is still limited and unsatisfactory. In solid tumors, NK cell function may be inhibited via different mechanisms, occurring primarily at the tumor site. The cellular interactions in the tumor microenvironment involve tumor cells, stromal cells and resident or recruited leukocytes and may favor tumor evasion from the host's defenses. In this context, a number of cytokines, growth factors and enzymes synthesized by tumor cells, stromal cells, suppressive/regulatory myeloid and lymphoid cells may substantially impair the function of different tumor-reactive effector cells, including NK cells. The identification and characterization of such mechanisms may offer clues for the development of new immunotherapeutic strategies to restore effective anti-tumor responses. In order to harness NK cell-based immunotherapies, several approaches have been proposed, including reinforcement of NK cell cytotoxicity by means of specific cytokines, antibodies or drugs. These new tools may improve NK cell function and/or increase tumor susceptibility to NK-mediated killing. Hence, the integration of NK-based immunotherapies with conventional anti-tumor therapies may increase chances of successful cancer treatment.
- Published
- 2016
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32. Unique Eomes(+) NK Cell Subsets Are Present in Uterus and Decidua During Early Pregnancy.
- Author
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Montaldo E, Vacca P, Chiossone L, Croxatto D, Loiacono F, Martini S, Ferrero S, Walzer T, Moretta L, and Mingari MC
- Abstract
Decidual and uterine natural killer (NK) cells have been shown to contribute to the successful pregnancy both in humans and mice. NK cells represent "cytotoxic" group 1 innate lymphoid cells (ILCs) and are distinct from the recently described "helper" ILC1. Here, we show that both in humans and mice the majority of group 1 ILC in endometrium/uterus and decidua express Eomesodermin (Eomes), thus suggesting that they are developmentally related to conventional NK cells. However, they differ from peripheral NK cells. In humans, Eomes(+) decidual NK (dNK) cells express CD49a and other markers of tissue residency, including CD103, integrin β7, CD9, and CD69. The expression of CD103 allows the identification of different subsets of IFNγ-producing Eomes(+) NK cells. We show that TGFβ can sustain/induce CD103 and CD9 expression in dNK cells and decidual CD34-derived NK cells, indicating that the decidual microenvironment can instruct the phenotype of Eomes(+) NK cells. In murine decidua and uterus, Eomes(+) cells include CD49a(-)CD49b(+) conventional NK cells and CD49a(+) cells. Notably, Eomes(+)CD49a(+) cells are absent in spleen and liver. Decidual and uterine Eomes(+)CD49a(+) cells can be dissected in two peculiar cell subsets according to CD49b expression. CD49a(+)CD49b ((-)) and CD49a(+)CD49b(+) cells are enriched in immature CD11b(low)CD27(high) cells, while CD49a(-)CD49b(+) cells contain higher percentages of mature CD11b(high)CD27(low) cells, both in uterus and decidua. Moreover, Eomes(+)CD49a(+)CD49b(-) cells decrease during gestation, thus suggesting that this peculiar subset may be required in early pregnancy rather than on later phases. Conversely, a minor Eomes(-)CD49a(+) ILC1 population present in decidua and uterus increases during pregnancy. CD49b(-)Eomes(±) cells produce mainly TNF, while CD49a(-)CD49b(+) conventional NK cells and CD49a(+)CD49b(+) cells produce both IFNγ and TNF. Thus, human and murine decidua contains unique subsets of group 1 ILCs, including Eomes(+) and Eomes(-) cells, with peculiar phenotypic and functional features. Our study contributes to re-examination of the complexity of uterine and decidual ILC subsets in humans and mice and highlights the role of the decidual microenvironment in shaping the features of these cells.
- Published
- 2016
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33. MSC and innate immune cell interactions: A lesson from human decidua.
- Author
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Vacca P, Montaldo E, Vitale C, Croxatto D, Moretta L, and Mingari MC
- Subjects
- Decidua cytology, Female, Humans, Immune System cytology, Mesenchymal Stem Cells cytology, Models, Immunological, Placenta cytology, Placenta immunology, Pregnancy, Stromal Cells cytology, Cell Communication immunology, Decidua immunology, Immune System immunology, Mesenchymal Stem Cells immunology, Stromal Cells immunology
- Abstract
Both experimental and clinical studies revealed that stromal cells (SC) are present in decidua (DSC) and placenta (PSC) at the early and late phase of pregnancy, respectively, and they may contribute to the induction of an anti-inflammatory/tolerogenic microenvironment crucial for the establishment/maintenance of successful pregnancy. These cells share common features with mesenchymal SC. In the present contribution, we provide an overall view on DSC features and on their ability to recruit NK cells and to regulate both differentiation and function not only of NK cells but also of CD14(+) myeloid cells. NK cells represent the large majority of leukocytes populating decidual tissues during the first trimester of pregnancy. Their cross-talk with DSC is thought to play a key role in the establishment of feto-maternal tolerance. We also discuss recent data suggesting that DSC may contribute to tissue remodeling, placentation, and recruitment of leukocytes also through their interaction with innate lymphoid cells (ILC) such as ILC3, that have recently been shown to be present in decidual tissue., (Copyright © 2015 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.)
- Published
- 2015
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34. Group 3 innate lymphoid cells (ILC3s): Origin, differentiation, and plasticity in humans and mice.
- Author
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Montaldo E, Juelke K, and Romagnani C
- Subjects
- Animals, Humans, Interleukin-17 immunology, Lymphocytes cytology, Mice, Interleukin-22, Gene Expression Regulation immunology, Immunity, Innate physiology, Interleukins immunology, Lymphocytes immunology, Nuclear Receptor Subfamily 1, Group F, Member 3 immunology
- Abstract
Since their discovery, innate lymphoid cells (ILCs) have been the subject of intense research. As their name implies, ILCs are innate cells of lymphoid origin, and can be grouped into subsets based on their cytotoxic activity, cytokine profile, and the transcriptional requirements during ILC differentiation. The main ILC groups are "killer" ILCs, comprising NK cells, and "helper-like" ILCs (including ILC1s, ILC2s, and ILC3s). This review examines the origin, differentiation stages, and plasticity of murine and human ILC3s. ILC3s express the retinoic acid receptor (RAR) related orphan receptor RORγt and the signature cytokines IL-22 and IL-17. Fetal ILC3s or lymphoid tissue inducer cells are required for lymphoid organogenesis, while postnatally developing ILC3s are important for the generation of intestinal cryptopatches and isolated lymphoid follicles as well as for the defence against pathogens and epithelial homeostasis. Here, we discuss the transcription factors and exogenous signals (including cytokines, nutrients and cell-to-cell interaction) that drive ILC3 lineage commitment and acquisition of their distinctive effector program., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2015
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35. IL-1β-releasing human acute myeloid leukemia blasts modulate natural killer cell differentiation from CD34+ precursors.
- Author
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Vitale C, Ambrosini P, Montaldo E, Ballerini F, Moretta L, and Mingari MC
- Subjects
- Adult, Aged, Blotting, Western, Case-Control Studies, Cell Proliferation, Cells, Cultured, Female, Fetal Blood metabolism, Flow Cytometry, Humans, Killer Cells, Natural drug effects, Killer Cells, Natural immunology, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute immunology, Male, Middle Aged, Phenotype, Antigens, CD34 metabolism, Cell Differentiation, Fetal Blood cytology, Interleukin-1beta pharmacology, Killer Cells, Natural pathology, Leukemia, Myeloid, Acute pathology
- Published
- 2015
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- View/download PDF
36. Human RORγt(+)CD34(+) cells are lineage-specified progenitors of group 3 RORγt(+) innate lymphoid cells.
- Author
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Montaldo E, Teixeira-Alves LG, Glatzer T, Durek P, Stervbo U, Hamann W, Babic M, Paclik D, Stölzel K, Gröne J, Lozza L, Juelke K, Matzmohr N, Loiacono F, Petronelli F, Huntington ND, Moretta L, Mingari MC, and Romagnani C
- Subjects
- Adult, Antigens, CD34 metabolism, Cell Differentiation, Cell Lineage, Cells, Cultured, Humans, Immunity, Innate, Interleukins metabolism, Intestines immunology, Killer Cells, Natural physiology, Microarray Analysis, Nuclear Receptor Subfamily 1, Group F, Member 3 genetics, Palatine Tonsil immunology, Signal Transduction, Interleukin-22, Hematopoietic Stem Cells physiology, Lymphocytes physiology, Nuclear Receptor Subfamily 1, Group F, Member 3 metabolism
- Abstract
Group 3 innate lymphoid cells (ILC3s) are defined by the expression of the transcription factor RORγt, which is selectively required for their development. The lineage-specified progenitors of ILC3s and their site of development after birth remain undefined. Here we identified a population of human CD34(+) hematopoietic progenitor cells (HPCs) that express RORγt and share a distinct transcriptional signature with ILC3s. RORγt(+)CD34(+) HPCs were located in tonsils and intestinal lamina propria (LP) and selectively differentiated toward ILC3s. In contrast, RORγt(-)CD34(+) HPCs could differentiate to become either ILC3s or natural killer (NK) cells, with differentiation toward ILC3 lineage determined by stem cell factor (SCF) and aryl hydrocarbon receptor (AhR) signaling. Thus, we demonstrate that in humans RORγt(+)CD34(+) cells are lineage-specified progenitors of IL-22(+) ILC3s and propose that tonsils and intestinal LP, which are enriched both in committed precursors and mature ILC3s, might represent preferential sites of ILC3 lineage differentiation., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
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37. Development of human natural killer cells and other innate lymphoid cells.
- Author
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Montaldo E, Vacca P, Moretta L, and Mingari MC
- Subjects
- Animals, Cell Differentiation immunology, Humans, Killer Cells, Natural cytology, Killer Cells, Natural metabolism, Lymphocyte Subsets cytology, Lymphocyte Subsets metabolism, Immunity, Innate physiology, Killer Cells, Natural immunology, Lymphocyte Subsets immunology
- Abstract
Innate lymphoid cells (ILC) have recently gained much attention in immunology. They represent a novel developmentally related family. Three distinct subsets have been identified on the basis of phenotypic and functional criteria and termed ILC1, ILC2, and ILC3. The available data suggest that ILC play an important role in innate defenses against different pathogens, in lymphoid organogenesis, and in tissue remodeling. All these aspects are relevant in hematopoietic stem cell transplantation (HSCT), particularly in the haplo-HSCT setting, in which donor NK cells are known to play a major therapeutic role, while the involvement of other ILC is still undefined. In this context, it has been postulated that all ILC share a common precursor expressing the ID2 transcription factor. While the differentiation of human NK cells (belonging to ILC1) is now well characterized both in vitro and in vivo, limited information is available on the development of human ILC2 and ILC3 and of their relationships with NK cells. In this review, we will summarize the present knowledge on the developmental relationship among different ILC, with particular focus on early stages of NK cell differentiation, and their features shared with ILC2 and ILC3., (Copyright © 2014 Elsevier Ltd. All rights reserved.)
- Published
- 2014
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38. Human NK cells: from surface receptors to the therapy of leukemias and solid tumors.
- Author
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Moretta L, Pietra G, Montaldo E, Vacca P, Pende D, Falco M, Del Zotto G, Locatelli F, Moretta A, and Mingari MC
- Abstract
Natural Killer (NK) cells are major effector cells of the innate immunity. The discovery, over two decades ago, of major histocompatibility complex-class I-specific inhibitory NK receptors and subsequently of activating receptors, recognizing ligands expressed by tumor or virus-infected cells, paved the way to our understanding of the mechanisms of selective recognition and killing of tumor cells. Although NK cells can efficiently kill tumor cells of different histotypes in vitro, their activity may be limited in vivo by their inefficient trafficking to tumor lesions and by the inhibition of their function induced by tumor cells themselves and by the tumor microenvironment. On the other hand, the important role of NK cells has been clearly demonstrated in the therapy of high risk leukemias in the haploidentical hematopoietic stem cell (HSC) transplantation setting. NK cells derived from donor HSC kill leukemic cells residual after the conditioning regimen, thus preventing leukemia relapses. In addition, they also kill residual dendritic cells and T lymphocytes, thus preventing both GvH disease and graft rejection.
- Published
- 2014
- Full Text
- View/download PDF
39. Human natural killer cells: origin, receptors, function, and clinical applications.
- Author
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Moretta L, Montaldo E, Vacca P, Del Zotto G, Moretta F, Merli P, Locatelli F, and Mingari MC
- Subjects
- HLA Antigens immunology, Humans, Leukemia immunology, Neoplasms immunology, Virus Diseases immunology, Immunity, Innate, Killer Cells, Natural immunology
- Abstract
Natural killer (NK) cells are important effectors playing a relevant role in innate immunity, primarily in tumor surveillance and in defenses against viruses. Human NK cells recognize HLA class I molecules through surface receptors (KIR and NKG2A) that inhibit NK cell function and kill target cells that have lost (or underexpress) HLA class I molecules as it occurs in tumors or virus-infected cells. NK cell activation is mediated by an array of activating receptors and co-receptors that recognize ligands expressed primarily on tumors or virus-infected cells. In vivo anti-tumor NK cell activity may be suppressed by tumor or tumor-associated cells. Alloreactive NK cells (i.e. those that are not inhibited by the HLA class I alleles of the patient) derived from HSC of haploidentical donors play a major role in the cure of high-risk leukemia, by killing leukemia blasts and patient's DC, thus preventing tumor relapses and graft-versus-host disease. The expression of the HLA-C2-specific activating KIR2DS1 may also contribute to NK alloreactivity in patients expressing C2 alleles. A clear correlation has been proven between the size of the alloreactive NK cell population and the clinical outcome. Recently, haplo-HSCT has been further improved with the direct infusion, together with HSC, of donor-derived, mature alloreactive NK cells and TCRγδ(+) T cells - both contributing to a prompt anti-leukemia effect together with an efficient defense against pathogens during the 6- to 8-week interval required for the generation of alloreactive NK cells from HSC., (© 2014 S. Karger AG, Basel.)
- Published
- 2014
- Full Text
- View/download PDF
40. Understanding human NK cell differentiation: clues for improving the haploidentical hematopoietic stem cell transplantation.
- Author
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Montaldo E, Vacca P, Moretta L, and Mingari MC
- Subjects
- Animals, Cell Differentiation, Haplotypes, Histocompatibility, Humans, Killer Cells, Natural transplantation, Leukemia immunology, Hematopoietic Stem Cell Transplantation, Killer Cells, Natural immunology, Leukemia therapy, Lymphoid Progenitor Cells immunology, Quality Improvement
- Abstract
The study of in vitro and in vivo NK cell differentiation from hematopoietic precursors revealed the existence of discrete stages of development. These stages are characterized by the progressive acquisition of markers and receptors that play a crucial role in NK cell function. The knowledge acquired has revealed particularly relevant for improving the HSCT to cure high-risk leukemias in the haplo-HSCT setting, in which NK cells play a central role in the clearance of leukemic cells and in the positive clinical outcome., (Copyright © 2013 Elsevier B.V. All rights reserved.)
- Published
- 2013
- Full Text
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41. Human NK cell receptors/markers: a tool to analyze NK cell development, subsets and function.
- Author
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Montaldo E, Del Zotto G, Della Chiesa M, Mingari MC, Moretta A, De Maria A, and Moretta L
- Subjects
- Animals, Antigens, CD metabolism, Biomarkers metabolism, Cell Differentiation, Cytomegalovirus Infections immunology, HIV Infections immunology, Hepatitis C immunology, Humans, Killer Cells, Natural physiology, Killer Cells, Natural virology, Phenotype, Receptors, Immunologic metabolism, Killer Cells, Natural metabolism
- Abstract
Natural killer (NK) cells are important components of the innate immunity and play a key role in host defense by virtue of their ability to release cytokines and to mediate cytolytic activity against tumor cells and virus-infected cells. NK cells were first described more than 30 years ago on the basis of their peculiar functional capabilities. Subsequently, thanks to the production of a variety of monoclonal antibodies, it became possible to identify surface receptors and markers expressed by NK cells as well as to characterize their functional properties. Here, we provide a brief historical overview about the discovery of human NK cell receptors and we delineate the main phenotypic features of differentiating and mature NK cells in healthy donors as well as their alterations in certain pathologic conditions., (Copyright © 2013 International Society for Advancement of Cytometry.)
- Published
- 2013
- Full Text
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42. Human NK cells at early stages of differentiation produce CXCL8 and express CD161 molecule that functions as an activating receptor.
- Author
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Montaldo E, Vitale C, Cottalasso F, Conte R, Glatzer T, Ambrosini P, Moretta L, and Mingari MC
- Subjects
- Antibodies, Monoclonal immunology, Antibodies, Monoclonal metabolism, Cell Survival, Cells, Cultured, Cytokines metabolism, Enzyme-Linked Immunosorbent Assay, Fetal Blood cytology, Flow Cytometry, Humans, Interleukin-8 genetics, NK Cell Lectin-Like Receptor Subfamily B genetics, RNA, Messenger genetics, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Cell Differentiation, Fetal Blood metabolism, Interleukin-8 metabolism, Killer Cells, Natural cytology, Killer Cells, Natural metabolism, NK Cell Lectin-Like Receptor Subfamily B metabolism
- Abstract
Human natural killer (NK) cell development is a step-by-step process characterized by phenotypically identified stages. CD161 is a marker informative of the NK cell lineage commitment, whereas CD56, CD117, and CD94/NKG2A contribute to define discrete differentiation stages. In cells undergoing in vitro differentiation from CD34(+) umbilical cord blood (UCB) progenitors, LFA-1 expression allowed to discriminate between immature noncytolytic CD161(+)CD56(+)LFA-1(-) and more differentiated cytolytic CD161(+)CD56(+)LFA-1(+) NK cells. CD161(+)CD56(+)LFA-1(-) NK cells produce large amounts of CXCL8 after phorbol myristate acetate (PMA) or cytokine treatment. Remarkably, CXCL8 mRNA expression was also detected in fresh stage III immature NK cells isolated from tonsils and these cells expressed CXCL8 protein on PMA stimulation. Within in vitro UCB-derived CD161(+)CD56(+)LFA-1(-) NK cells, CXCL8 release was also induced on antibody-mediated cross-linking of NKp44 and CD161. Such unexpected activating function of CD161 was confined to the CD161(+)CD56(+)LFA-1(-) subset, because it did not induce cytokine release or CD107a expression in CD161(+)CD56(+)LFA-1(+) cells or in mature peripheral blood NK cells. Anti-CXCL8 neutralizing antibody induced a partial inhibition of NK cell differentiation, which suggests a regulatory role of CXCL8 during early NK cell differentiation. Altogether, these data provide novel information that may offer clues to optimize NK cell maturation in hematopoietic stem cell transplantation.
- Published
- 2012
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43. CD34+ hematopoietic precursors are present in human decidua and differentiate into natural killer cells upon interaction with stromal cells.
- Author
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Vacca P, Vitale C, Montaldo E, Conte R, Cantoni C, Fulcheri E, Darretta V, Moretta L, and Mingari MC
- Subjects
- Adult, Antigens, Differentiation immunology, Cells, Cultured, Coculture Techniques, Female, Gene Expression Regulation immunology, Humans, Organ Specificity immunology, Pregnancy, Stromal Cells cytology, Stromal Cells immunology, Antigens, CD34, Cell Communication immunology, Decidua cytology, Decidua immunology, Hematopoietic Stem Cells cytology, Hematopoietic Stem Cells immunology, Killer Cells, Natural cytology, Killer Cells, Natural immunology
- Abstract
Natural killer (NK) cells are the main lymphoid population in the maternal decidua during the first trimester of pregnancy. Decidual NK (dNK) cells display a unique functional profile and play a key role in promoting tissue remodeling, neoangiogenesis, and immune modulation. However, little information exists on their origin and development. Here we discovered CD34(+) hematopoietic precursors in human decidua (dCD34(+)). We show that dCD34(+) cells differ from cord blood- or peripheral blood-derived CD34(+) precursors. The expression of IL-15/IL-2 receptor common β-chain (CD122), IL-7 receptor α-chain (CD127), and mRNA for E4BP4 and ID2 transcription factors suggested that dCD34(+) cells are committed to the NK cell lineage. Moreover, they could undergo in vitro differentiation into functional (i.e., IL-8- and IL-22-producing) CD56(bright)CD16(-)KIR(+/-) NK cells in the presence of growth factors or even upon coculture with decidual stromal cells. Their NK cell commitment was further supported by the failure to undergo myeloid differentiation in the presence of GM-CSF. Our findings strongly suggest that decidual NK cells may directly derive from CD34(+) cell precursors present in the decidua upon specific cellular interactions with components of the decidual microenvironment.
- Published
- 2011
- Full Text
- View/download PDF
44. Immune response in the conjunctival epithelium of patients with dry eye.
- Author
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Barabino S, Montaldo E, Solignani F, Valente C, Mingari MC, and Rolando M
- Subjects
- Adult, Antigens, CD metabolism, B-Lymphocytes immunology, CD4-Positive T-Lymphocytes immunology, Cell Count, Female, Flow Cytometry, HLA-DR Antigens immunology, Humans, Immunophenotyping, Keratin-19 metabolism, Killer Cells, Natural immunology, Male, Middle Aged, Conjunctiva immunology, Dry Eye Syndromes immunology, Epithelium immunology, Immune System physiology
- Abstract
The aim of our project was to test the hypothesis that patients with dry eye have a significant degree of inflammation and lymphocyte infiltration in conjunctival epithelium by using flow cytometry analysis of cells stored in cell culture medium. Impression cytology specimens were collected in 15 normal subjects and 15 dry eye patients. Samples collected from the right eye were placed in Phosphate Buffered Saline containing 0.05% paraformaldehyde (PFA), and samples from the left eye in cell culture medium containing 10% foetal calf serum (FCS). Phenotypic analysis was performed on cells derived from 21 dry eye patients and 16 healthy controls. The cells collected in FCS were stained for the expression of CK19, CD3, CD4, CD8, CD56, CD19, CD20, CD14 and HLA-DR, and analyzed by flow cytometry. FCS samples contained a statistically increased number of cells when compared to PFA samples. No statistically significant differences were present in the number of CD45+CK19- cells, CD3+ and CD4+T cells, B and NK cells in dry eye patients compared to healthy controls. In the dry eye group there was a significant difference in the CD4/CD8 ratio respect to what observed in normal subjects, and an increased number of CD14+ cells. HLA-DR expression was increased only in CK19+ conjunctival epithelial cells of dry eye patients. This study indicates that immune cells isolated from the superficial layer of the conjunctiva may play a pivotal role in the pathogenesis of dry eye, and that a new method of preservation of impression cytology samples can enhance flow cytometry analysis of epithelial and immune cells of the conjunctiva.
- Published
- 2010
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- View/download PDF
45. Quantitative evaluation of ocular surface inflammation in patients with different grade of conjunctivochalasis.
- Author
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Fodor E, Barabino S, Montaldo E, Mingari MC, and Rolando M
- Subjects
- Biomarkers metabolism, Coloring Agents metabolism, Conjunctiva pathology, Conjunctival Diseases classification, Conjunctival Diseases pathology, Epithelial Cells pathology, Female, Flow Cytometry, Humans, Inflammation metabolism, Lissamine Green Dyes metabolism, Male, Middle Aged, Staining and Labeling, Conjunctiva metabolism, Conjunctival Diseases metabolism, Epithelial Cells metabolism, HLA-DR Antigens metabolism
- Abstract
Purpose: To evaluate and compare HLA-DR expression of conjunctival epithelial cells in different grade of conjunctivochalasis (CCh)., Patients and Methods: Thirty patients and seven healthy subjects underwent clinical examination, grading of CCh by lid-parallel conjunctival fold (LIPCOF) test, and impression cytology of the bulbar conjunctiva. HLA-DR expression was analyzed by flow cytometry. Schirmer test, tear break-up time, and vital staining were also performed., Results: Patients who presented with mild and moderate CCh showed a similar expression of HLA-DR to normal subjects. A significant increase (p < 0.005) of HLA-DR was found in patients with severe CCh. Positive correlation was found between fluorescein staining and HLA-DR expression (r = 0.36, p = 0.009) and between lissamine-green staining and HLA-DR expression (r = 0.30, p = 0.027). Neither correlation was found between Schirmer test nor break up time and HLA-DR expression., Conclusion: Inflammation plays a pivotal role on the ocular surface of patients with severe CCh. Since mild and moderate CCh HLA-DR expression was similar to normal controls, we can speculate that the source of inflammation could be the presence of conjunctival folds.
- Published
- 2010
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46. Beta-thalassaemia control.
- Author
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Zorcolo G, Landis N, Madeddu E, Mandas G, Montaldo E, Perisi S, Piras G, Salemi L, and Sicilia R
- Subjects
- Female, Fetal Diseases diagnosis, Genetic Carrier Screening, Genetic Counseling, Humans, Italy, Pregnancy, Prenatal Diagnosis, Thalassemia diagnosis, Thalassemia prevention & control
- Published
- 1986
- Full Text
- View/download PDF
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