Publications by authors named "Lorenzo Cosmi"

93 Publications

Metabolomic/lipidomic profiling of COVID-19 and individual response to tocilizumab.

PLoS Pathog 2021 02 1;17(2):e1009243. Epub 2021 Feb 1.

Magnetic Resonance Center (CERM), University of Florence, Sesto Fiorentino, Florence, Italy.

The current pandemic emergence of novel coronavirus disease (COVID-19) poses a relevant threat to global health. SARS-CoV-2 infection is characterized by a wide range of clinical manifestations, ranging from absence of symptoms to severe forms that need intensive care treatment. Here, plasma-EDTA samples of 30 patients compared with age- and sex-matched controls were analyzed via untargeted nuclear magnetic resonance (NMR)-based metabolomics and lipidomics. With the same approach, the effect of tocilizumab administration was evaluated in a subset of patients. Despite the heterogeneity of the clinical symptoms, COVID-19 patients are characterized by common plasma metabolomic and lipidomic signatures (91.7% and 87.5% accuracy, respectively, when compared to controls). Tocilizumab treatment resulted in at least partial reversion of the metabolic alterations due to SARS-CoV-2 infection. In conclusion, NMR-based metabolomic and lipidomic profiling provides novel insights into the pathophysiological mechanism of human response to SARS-CoV-2 infection and to monitor treatment outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.ppat.1009243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877736PMC
February 2021

Innate lymphoid cells type 2 in LTP-allergic patients and their modulation during sublingual immunotherapy.

Allergy 2021 Jan 21. Epub 2021 Jan 21.

Allergy Research Group, Instituto de Investigación Biomédica de Málaga-IBIMA, Málaga, Spain.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/all.14745DOI Listing
January 2021

Group 2 Innate Lymphoid Cells: A Double-Edged Sword in Cancer?

Cancers (Basel) 2020 Nov 20;12(11). Epub 2020 Nov 20.

Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy.

Group 2 Innate Lymphoid Cells (ILC2s) belong to the family of helper ILCs which provide host defense against infectious agents, participate in inflammatory responses and mediate lymphoid organogenesis and tissue repair, mainly at the skin and mucosal level. Based on their transcriptional, phenotypic and functional profile, ILC2s mirror the features of the adaptive CD4+ Th2 cell subset, both contributing to the so-called type 2 immune response. Similar to other ILCs, ILC2s are rapidly activated by signals deriving from tissue and/or other tissue-resident immune cells. The biologic activity of ILCs needs to be tightly regulated in order to prevent them from contributing to severe inflammation and damage in several organs. Indeed, ILC2s display both enhancing and regulatory roles in several pathophysiological conditions, including tumors. In this review, we summarize the actual knowledge about ILC2s ability to induce or impair a protective immune response, their pro- or antitumor activity in murine models, human (children and adults) pathologies and the potential strategies to improve cancer immunotherapy by exploiting the features of ILC2s.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers12113452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699723PMC
November 2020

Pulmonary vascular improvement in severe COVID-19 patients treated with tocilizumab.

Immunol Lett 2020 12 5;228:122-128. Epub 2020 Nov 5.

Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy; Immunology and Cell Therapy Unit, Careggi University Hospital, Florence, Italy. Electronic address:

As of October 2020 management of Coronavirus disease 2019 (COVID-19) is based on supportive care and off-label or compassionate-use therapies. On March 2020 tocilizumab - an anti-IL-6 receptor monoclonal antibody - was suggested as immunomodulatory treatment in severe COVID-19 because hyperinflammatory syndrome occurs in many patients similarly to the cytokine release syndrome that develops after CAR-T cell therapy. In our retrospective observational study, 20 severe COVID-19 patients requiring intensive care were treated with tocilizumab in addition to standard-of-care therapy (SOC) and compared with 13 COVID-19 patients receiving only SOC. Clinical respiratory status, inflammatory markers and vascular radiologic score improved after one week from tocilizumab administration. On the contrary, these parameters were stable or worsened in patients receiving only SOC. Despite major study limitations, improvement of alveolar-arterial oxygen gradient as well as vascular radiologic score after one week may account for improved pulmonary vascular perfusion and could explain the more rapid recovery of COVID-19 patients receiving tocilizumab compared to controls.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.imlet.2020.10.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7644186PMC
December 2020

Cell-mediated and humoral adaptive immune responses to SARS-CoV-2 are lower in asymptomatic than symptomatic COVID-19 patients.

Eur J Immunol 2020 Dec 9;50(12):2013-2024. Epub 2020 Nov 9.

Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.

The characterization of cell-mediated and humoral adaptive immune responses to SARS-CoV-2 is fundamental to understand COVID-19 progression and the development of immunological memory to the virus. In this study, we detected T-cells reactive to SARS-CoV-2 proteins M, S, and N, as well as serum virus-specific IgM, IgA, IgG, in nearly all SARS-CoV-2 infected individuals, but not in healthy donors. Virus-reactive T cells exhibited signs of in vivo activation, as suggested by the surface expression of immune-checkpoint molecules PD1 and TIGIT. Of note, we detected antigen-specific adaptive immune response both in asymptomatic and symptomatic SARS-CoV-2 infected subjects. More importantly, symptomatic patients displayed a significantly higher magnitude of both cell-mediated and humoral adaptive immune response to the virus, as compared to asymptomatic individuals. These findings suggest that an uncontrolled adaptive immune response contribute to the development of the life-threatening inflammatory phase of the disease. Finally, this study might open the way to develop effective vaccination strategies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/eji.202048915DOI Listing
December 2020

Oral CorticoSteroid sparing with biologics in severe asthma: A remark of the ().

World Allergy Organ J 2020 Oct 20;13(10):100464. Epub 2020 Sep 20.

Personalized Medicine, Asthma & Allergy, Humanitas Clinical and Research Center, IRCCS, Rozzano, MI, Italy.

According to the data derived from several national and international registries, including SANI (Severe Asthma Network Italy), and considering the strong impact that frequent or regular use of oral corticosteroid has on quality of life (QoL) of severe asthmatics, as well as on the costs for managing corticosteroid-related diseases, oral corticosteroid sparing up to withdrawal should be considered a primary outcome in the management of severe asthma. New biologics have clearly demonstrated that this effect is possible, with concomitant reduction in the rate of exacerbations and in symptom control. Then, there is no reason for using so frequently oral corticosteroid before having explored all alternatives currently available for a large part of severe asthmatics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.waojou.2020.100464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509464PMC
October 2020

Quantitative and qualitative alterations of circulating myeloid cells and plasmacytoid DC in SARS-CoV-2 infection.

Immunology 2020 12 6;161(4):345-353. Epub 2020 Oct 6.

Flow Cytometry Diagnostic Center and Immunotherapy (CDCI), AOU Careggi, Florence, Italy.

SARS-CoV-2 is responsible for a new infectious disease (COVID-19) in which individuals can either remain asymptomatic or progress from mild to severe clinical conditions including acute respiratory distress syndrome and multiple organ failure. The immune mechanisms that potentially orchestrate the pathology in SARS-CoV-2 infection are complex and only partially understood. There is still paucity of data on the features of myeloid cells involved in this viral infection. For this reason, we investigated the different activation status profiles and the subset distribution of myeloid cells and their correlation with disease progression in 40 COVID-19 patients at different stages of disease. COVID-19 patients showed a decrease in the absolute number of plasmacytoid and myeloid dendritic cells, different subset distribution of monocytes and different activation patterns of both monocytes and neutrophils, coupled to a significant reduction of HLA-DR monocyte levels. We found that some of these alterations are typical of all COVID-19 patients, while some others vary at different stages of the disease and correlate with biochemical parameters of inflammation. Collectively, these data suggest that not only the lymphoid, but also the myeloid compartment, is severely affected by SARS-CoV-2 infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/imm.13254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692244PMC
December 2020

Plasticity and regulatory mechanisms of human ILC2 functions.

Immunol Lett 2020 11 18;227:109-116. Epub 2020 Aug 18.

Department of Experimental and Clinical Medicine and DENOTHE Center, University of Florence, Florence, 50134, Italy.

Human group 2 innate lymphoid cells (ILC2) represent the innate counterpart of Th2 cells and cooperate with them in helminths protection and in the pathogenesis of allergic diseases. Some reports described ILC2 plasticity and few studies investigated the cellular and molecular mechanisms regulating human ILC2 functions. The aim of this study is to define how immune deviation and immune regulation control human ILC2-mediated immune response. Human circulating ILC2 were expanded in vitro and then cultured in presence of IL-12 or IL-1β plus IL-23 or co-coltured in presence of circulating CD4+CD25highFoxp3+Treg. IL-12 induces IFN-γ production and upregulation of T-bet mRNA level on human circulating ILC2 whereas IL-1β and IL-23 mediate IL-22 production and upregulation of RORC mRNA level. In all these conditions, GATA-3 mRNA level is not reduced and the typical type 2 cytokines are only partially reduced. Moreover, "modulated" ILC2 have reduced ability to induce IgE producing by B cells. ILC2 proliferation, cytokines production and CD154 expression were inhibited by CD4+CD25highFoxp3+ Treg cells. TGF-β reduced CD154 expression on ILC2 stimulated with IL-25/IL-33. This study defines possible cellular and molecular mechanisms responsible for modulation and inhibition of human ILC2 activity. These results may be useful in the development of strategies aimed to dampen ILC2 function in type-2 mediated diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.imlet.2020.08.004DOI Listing
November 2020

Th17 lymphocyte-dependent degradation of joint cartilage by synovial fibroblasts in a humanized mouse model of arthritis and reversal by secukinumab.

Eur J Immunol 2021 Jan 9;51(1):220-230. Epub 2020 Aug 9.

Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy.

How T-helper (Th) lymphocyte subpopulations identified in synovial fluid from patients with juvenile idiopathic arthritis (JIA) (Th17, classic Th1, or nonclassic Th1) drive joint damage is of great interest for the possible use of biological drugs that inhibit the specific cytokines. Our objective was to clarify the role of such Th subpopulations in the pathogenesis of articular cartilage destruction by synovial fibroblasts (SFbs), and the effect of Th17 blockage in an animal model. SFbs were isolated from healthy subjects and patients with JIA, and peripheral blood Th lymphocytes subsets were obtained from healthy subjects. Fragments of human cartilage from healthy subjects in a collagen matrix containing JIA or normal SFbs grafted underskin in SCID mice were used to measure cartilage degradation under the effects of Th supernatants. JIA SFbs overexpress MMP9 and MMP2 and Th17 induce both MMPs in normal SFbs, while nonclassic Th1 upregulate urokinase plasminogen activator (uPA) activity. In vitro invasive phenotype of normal SFbs is stimulated with conditioned medium of Th17 and nonclassic-Th1. In the in vivo "inverse wrap" model, normal SFbs stimulated with supernatants of Th17-lymphocytes and nonclassic Th1 produced a cartilage invasion and degradation similar to JIA SFbs. Secukinumab inhibits the cartilage damage triggered by factors produced by Th17.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/eji.202048773DOI Listing
January 2021

Prompt Predicting of Early Clinical Deterioration of Moderate-to-Severe COVID-19 Patients: Usefulness of a Combined Score Using IL-6 in a Preliminary Study.

J Allergy Clin Immunol Pract 2020 Sep 19;8(8):2575-2581.e2. Epub 2020 Jun 19.

Immunoallergology Unit, Careggi University Hospital, Florence, Italy. Electronic address:

Background: The early identification of patients at risk of clinical deterioration is of interest considering the timeline of COVID-19 after the onset of symptoms.

Objective: The aim of our study was to evaluate the usefulness of testing serum IL-6 and other serological and clinical biomarkers, to predict a short-term negative clinical course of patients with noncritical COVID-19.

Methods: A total of 208 patients with noncritical COVID-19 pneumonia at admission were consecutively enrolled. Clinical and laboratory findings obtained on admission were analyzed by using survival analysis and stepwise logistic regression for variable selection. Three-day worsening as outcome in a logistic model to generate a prognostic score was used.

Results: Clinical worsening occurred in 63 patients (16 = died; 39 = transferred to intensive care unit; 8 worsening of respiratory failure). Forty-five of them worsened within 3 days after admission. The risk of clinical worsening was progressively enhanced along with increasing quartiles of IL-6 levels. Multivariate analysis showed that IL-6 (P = .005), C-reactive protein (CRP) (P = .003), and SaO/FiO (P = .014) were the best predictors for clinical deterioration in the first 3 days after admission. The combined score yielded an area under the curve = 0.88 (95% confidence interval: 0.83-0.93). A nomogram predicting the probability of 3-day worsening was generated. The score also showed good performance for 7-day and 14- or 21-day worsening and in predicting death occurring during all the follow-up.

Conclusions: Combining IL-6, CRP, and SaO/FiO in a score may help clinicians to identify on admission those patients with COVID-19 who are at high risk for a further 3-day clinical deterioration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaip.2020.06.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303032PMC
September 2020

Impaired immune cell cytotoxicity in severe COVID-19 is IL-6 dependent.

J Clin Invest 2020 09;130(9):4694-4703

Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.

BACKGROUNDCoronavirus disease 19 (COVID-19) is an emerging infectious disease caused by SARS-CoV-2. Antiviral immune response is crucial to achieve pathogen clearance; however, in some patients an excessive and aberrant host immune response can lead to an acute respiratory distress syndrome. The comprehension of the mechanisms that regulate pathogen elimination, immunity, and pathology is essential to better characterize disease progression and widen the spectrum of therapeutic options.METHODSWe performed a flow cytometric characterization of immune cell subsets from 30 patients with COVID-19 and correlated these data with clinical outcomes.RESULTSPatients with COVID-19 showed decreased numbers of circulating T, B, and NK cells and exhibited a skewing of CD8+ T cells toward a terminally differentiated/senescent phenotype. In agreement, CD4+ T and CD8+ T, but also NK cells, displayed reduced antiviral cytokine production capability. Moreover, a reduced cytotoxic potential was identified in patients with COVID-19, particularly in those who required intensive care. The latter group of patients also showed increased serum IL-6 levels that inversely correlated to the frequency of granzyme A-expressing NK cells. Off-label treatment with tocilizumab restored the cytotoxic potential of NK cells.CONCLUSIONThe association between IL-6 serum levels and the impairment of cytotoxic activity suggests the possibility that targeting this cytokine may restore antiviral mechanisms.FUNDINGThis study was supported by funds from the Department of Experimental and Clinical Medicine of University of Florence (the ex-60% fund and the "Excellence Departments 2018-2022 Project") derived from Ministero dell'Istruzione, dell'Università e della Ricerca (Italy).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/JCI138554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456250PMC
September 2020

Human T cells interacting with HNSCC-derived mesenchymal stromal cells acquire tissue-resident memory like properties.

Eur J Immunol 2020 10 2;50(10):1571-1579. Epub 2020 Jun 2.

Department of Experimental and Clinical Medicine, University of Florence, Firenze, Italy.

Tissue-resident memory (Trm) cells are specialized components of both CD4+ and CD8+ T cell subsets that persist in peripheral nonlymphoid tissues following infections and provide fast response in case of a secondary invasion by the same pathogen. Trm cells express the surface markers CD69, CD103, and the immune checkpoint molecule PD-1. Trm cells develop not only in the context of infections but also in tumors, where they can provide a line of defense as suggested by the positive correlation between the frequency of tumor-infiltrating Trm cells and patients' survival. Trm cells persistence in peripheral tissues depends on their adaptation to the local microenvironment and the presence of survival factors, mainly IL-7, IL-15, and Notch ligands. However, the cell sources of these factors are largely unknown, especially in the context of tumors. Here, we show that head-neck squamous cell carcinoma (HNSCC) is enriched in CD4+ and CD8+ T cells with a Trm phenotype. Moreover, we show that mesenchymal stromal cells that accumulate in HNSCC are a source of survival factors and allow proper expression of Trm-typical markers in a VCAM1-dependent manner.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/eji.202048544DOI Listing
October 2020

Guidelines for the use of flow cytometry and cell sorting in immunological studies (second edition).

Authors:
Andrea Cossarizza Hyun-Dong Chang Andreas Radbruch Andreas Acs Dieter Adam Sabine Adam-Klages William W Agace Nima Aghaeepour Mübeccel Akdis Matthieu Allez Larissa Nogueira Almeida Giorgia Alvisi Graham Anderson Immanuel Andrä Francesco Annunziato Achille Anselmo Petra Bacher Cosima T Baldari Sudipto Bari Vincenzo Barnaba Joana Barros-Martins Luca Battistini Wolfgang Bauer Sabine Baumgart Nicole Baumgarth Dirk Baumjohann Bianka Baying Mary Bebawy Burkhard Becher Wolfgang Beisker Vladimir Benes Rudi Beyaert Alfonso Blanco Dominic A Boardman Christian Bogdan Jessica G Borger Giovanna Borsellino Philip E Boulais Jolene A Bradford Dirk Brenner Ryan R Brinkman Anna E S Brooks Dirk H Busch Martin Büscher Timothy P Bushnell Federica Calzetti Garth Cameron Ilenia Cammarata Xuetao Cao Susanna L Cardell Stefano Casola Marco A Cassatella Andrea Cavani Antonio Celada Lucienne Chatenoud Pratip K Chattopadhyay Sue Chow Eleni Christakou Luka Čičin-Šain Mario Clerici Federico S Colombo Laura Cook Anne Cooke Andrea M Cooper Alexandra J Corbett Antonio Cosma Lorenzo Cosmi Pierre G Coulie Ana Cumano Ljiljana Cvetkovic Van Duc Dang Chantip Dang-Heine Martin S Davey Derek Davies Sara De Biasi Genny Del Zotto Gelo Victoriano Dela Cruz Michael Delacher Silvia Della Bella Paolo Dellabona Günnur Deniz Mark Dessing James P Di Santo Andreas Diefenbach Francesco Dieli Andreas Dolf Thomas Dörner Regine J Dress Diana Dudziak Michael Dustin Charles-Antoine Dutertre Friederike Ebner Sidonia B G Eckle Matthias Edinger Pascale Eede Götz R A Ehrhardt Marcus Eich Pablo Engel Britta Engelhardt Anna Erdei Charlotte Esser Bart Everts Maximilien Evrard Christine S Falk Todd A Fehniger Mar Felipo-Benavent Helen Ferry Markus Feuerer Andrew Filby Kata Filkor Simon Fillatreau Marie Follo Irmgard Förster John Foster Gemma A Foulds Britta Frehse Paul S Frenette Stefan Frischbutter Wolfgang Fritzsche David W Galbraith Anastasia Gangaev Natalio Garbi Brice Gaudilliere Ricardo T Gazzinelli Jens Geginat Wilhelm Gerner Nicholas A Gherardin Kamran Ghoreschi Lara Gibellini Florent Ginhoux Keisuke Goda Dale I Godfrey Christoph Goettlinger Jose M González-Navajas Carl S Goodyear Andrea Gori Jane L Grogan Daryl Grummitt Andreas Grützkau Claudia Haftmann Jonas Hahn Hamida Hammad Günter Hämmerling Leo Hansmann Goran Hansson Christopher M Harpur Susanne Hartmann Andrea Hauser Anja E Hauser David L Haviland David Hedley Daniela C Hernández Guadalupe Herrera Martin Herrmann Christoph Hess Thomas Höfer Petra Hoffmann Kristin Hogquist Tristan Holland Thomas Höllt Rikard Holmdahl Pleun Hombrink Jessica P Houston Bimba F Hoyer Bo Huang Fang-Ping Huang Johanna E Huber Jochen Huehn Michael Hundemer Christopher A Hunter William Y K Hwang Anna Iannone Florian Ingelfinger Sabine M Ivison Hans-Martin Jäck Peter K Jani Beatriz Jávega Stipan Jonjic Toralf Kaiser Tomas Kalina Thomas Kamradt Stefan H E Kaufmann Baerbel Keller Steven L C Ketelaars Ahad Khalilnezhad Srijit Khan Jan Kisielow Paul Klenerman Jasmin Knopf Hui-Fern Koay Katja Kobow Jay K Kolls Wan Ting Kong Manfred Kopf Thomas Korn Katharina Kriegsmann Hendy Kristyanto Thomas Kroneis Andreas Krueger Jenny Kühne Christian Kukat Désirée Kunkel Heike Kunze-Schumacher Tomohiro Kurosaki Christian Kurts Pia Kvistborg Immanuel Kwok Jonathan Landry Olivier Lantz Paola Lanuti Francesca LaRosa Agnès Lehuen Salomé LeibundGut-Landmann Michael D Leipold Leslie Y T Leung Megan K Levings Andreia C Lino Francesco Liotta Virginia Litwin Yanling Liu Hans-Gustaf Ljunggren Michael Lohoff Giovanna Lombardi Lilly Lopez Miguel López-Botet Amy E Lovett-Racke Erik Lubberts Herve Luche Burkhard Ludewig Enrico Lugli Sebastian Lunemann Holden T Maecker Laura Maggi Orla Maguire Florian Mair Kerstin H Mair Alberto Mantovani Rudolf A Manz Aaron J Marshall Alicia Martínez-Romero Glòria Martrus Ivana Marventano Wlodzimierz Maslinski Giuseppe Matarese Anna Vittoria Mattioli Christian Maueröder Alessio Mazzoni James McCluskey Mairi McGrath Helen M McGuire Iain B McInnes Henrik E Mei Fritz Melchers Susanne Melzer Dirk Mielenz Stephen D Miller Kingston H G Mills Hans Minderman Jenny Mjösberg Jonni Moore Barry Moran Lorenzo Moretta Tim R Mosmann Susann Müller Gabriele Multhoff Luis Enrique Muñoz Christian Münz Toshinori Nakayama Milena Nasi Katrin Neumann Lai Guan Ng Antonia Niedobitek Sussan Nourshargh Gabriel Núñez José-Enrique O'Connor Aaron Ochel Anna Oja Diana Ordonez Alberto Orfao Eva Orlowski-Oliver Wenjun Ouyang Annette Oxenius Raghavendra Palankar Isabel Panse Kovit Pattanapanyasat Malte Paulsen Dinko Pavlinic Livius Penter Pärt Peterson Christian Peth Jordi Petriz Federica Piancone Winfried F Pickl Silvia Piconese Marcello Pinti A Graham Pockley Malgorzata Justyna Podolska Zhiyong Poon Katharina Pracht Immo Prinz Carlo E M Pucillo Sally A Quataert Linda Quatrini Kylie M Quinn Helena Radbruch Tim R D J Radstake Susann Rahmig Hans-Peter Rahn Bartek Rajwa Gevitha Ravichandran Yotam Raz Jonathan A Rebhahn Diether Recktenwald Dorothea Reimer Caetano Reis e Sousa Ester B M Remmerswaal Lisa Richter Laura G Rico Andy Riddell Aja M Rieger J Paul Robinson Chiara Romagnani Anna Rubartelli Jürgen Ruland Armin Saalmüller Yvan Saeys Takashi Saito Shimon Sakaguchi Francisco Sala-de-Oyanguren Yvonne Samstag Sharon Sanderson Inga Sandrock Angela Santoni Ramon Bellmàs Sanz Marina Saresella Catherine Sautes-Fridman Birgit Sawitzki Linda Schadt Alexander Scheffold Hans U Scherer Matthias Schiemann Frank A Schildberg Esther Schimisky Andreas Schlitzer Josephine Schlosser Stephan Schmid Steffen Schmitt Kilian Schober Daniel Schraivogel Wolfgang Schuh Thomas Schüler Reiner Schulte Axel Ronald Schulz Sebastian R Schulz Cristiano Scottá Daniel Scott-Algara David P Sester T Vincent Shankey Bruno Silva-Santos Anna Katharina Simon Katarzyna M Sitnik Silvano Sozzani Daniel E Speiser Josef Spidlen Anders Stahlberg Alan M Stall Natalie Stanley Regina Stark Christina Stehle Tobit Steinmetz Hannes Stockinger Yousuke Takahama Kiyoshi Takeda Leonard Tan Attila Tárnok Gisa Tiegs Gergely Toldi Julia Tornack Elisabetta Traggiai Mohamed Trebak Timothy I M Tree Joe Trotter John Trowsdale Maria Tsoumakidou Henning Ulrich Sophia Urbanczyk Willem van de Veen Maries van den Broek Edwin van der Pol Sofie Van Gassen Gert Van Isterdael René A W van Lier Marc Veldhoen Salvador Vento-Asturias Paulo Vieira David Voehringer Hans-Dieter Volk Anouk von Borstel Konrad von Volkmann Ari Waisman Rachael V Walker Paul K Wallace Sa A Wang Xin M Wang Michael D Ward Kirsten A Ward-Hartstonge Klaus Warnatz Gary Warnes Sarah Warth Claudia Waskow James V Watson Carsten Watzl Leonie Wegener Thomas Weisenburger Annika Wiedemann Jürgen Wienands Anneke Wilharm Robert John Wilkinson Gerald Willimsky James B Wing Rieke Winkelmann Thomas H Winkler Oliver F Wirz Alicia Wong Peter Wurst Jennie H M Yang Juhao Yang Maria Yazdanbakhsh Liping Yu Alice Yue Hanlin Zhang Yi Zhao Susanne Maria Ziegler Christina Zielinski Jakob Zimmermann Arturo Zychlinsky

Eur J Immunol 2019 Oct;49(10):1457-1973

Max Planck Institute for Infection Biology, Berlin, Germany.

These guidelines are a consensus work of a considerable number of members of the immunology and flow cytometry community. They provide the theory and key practical aspects of flow cytometry enabling immunologists to avoid the common errors that often undermine immunological data. Notably, there are comprehensive sections of all major immune cell types with helpful Tables detailing phenotypes in murine and human cells. The latest flow cytometry techniques and applications are also described, featuring examples of the data that can be generated and, importantly, how the data can be analysed. Furthermore, there are sections detailing tips, tricks and pitfalls to avoid, all written and peer-reviewed by leading experts in the field, making this an essential research companion.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/eji.201970107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7350392PMC
October 2019

Biological and clinical significance of T helper 17 cell plasticity.

Immunology 2019 12 14;158(4):287-295. Epub 2019 Oct 14.

Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.

Mature T helper (Th) effector cells originate following antigen recognition by naive T precursors. The maturation process is accompanied by the acquisition of specific effector functions that distinguish at least three different T helper subsets: Th1, Th2 and Th17. In general, maturation of somatic cells is accompanied by terminal differentiation. However, accumulating evidence shows that effector T cells retain a certain degree of plasticity. This is especially true for Th17 cells, which have been shown to converge towards other phenotypes in response to specific microenvironmental pressure. In this review we will discuss the experimental evidence that supports the hypothesis of Th17 plasticity, with particular emphasis on the generation of Th17-derived 'non-classic' Th1 cells, and the molecular networks that control it. Moreover, we will consider why Th17 plasticity is important for host protection, but also why it can have pathogenic functions during chronic inflammation. Regarding the last point, we will discuss a possible role for biological drugs in the control of Th17 plasticity and disease course.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/imm.13124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6856928PMC
December 2019

The intestinal expansion of TCRγδ and disappearance of IL4 T cells suggest their involvement in the evolution from potential to overt celiac disease.

Eur J Immunol 2019 12 25;49(12):2222-2234. Epub 2019 Oct 25.

Institute of Biochemistry and Cell Biology, National Research Council, Naples, Italy.

Celiac disease (CD) is characterized by a spectrum of intestinal inflammatory lesions. Most patients have villous atrophy (overt-CD), while others have a morphologically normal mucosa, despite the presence of CD-specific autoantibodies (potential-CD). As the mechanism responsible for villous atrophy is not completely elucidated, we investigated biomarkers specific for the different celiac lesions. Phenotype and cytokine production of intestinal mucosa cells were analyzed by flow cytometry in gut biopsies of children with overt- or potential-CD and in healthy controls. Density of TCRγδ T cells was found markedly enhanced in intestinal mucosa of children with overt-CD compared to potential-CD or controls. By contrast, very few IL4 T cells infiltrated the mucosa with villous atrophy compared to morphologically normal mucosa. IL4 T cells were classical CD4 T-helper cells (CD161 ), producing or not IFN-γ, and negative for IL17A. Our study demonstrated that the transition to villous atrophy in CD patients is characterized by increased density of TCRγδ T cells, and concomitant disappearance of IL4 cells. These findings suggest that immunomodulatory mechanisms are active in potential-CD to counteract the inflammatory cascade responsible of villous atrophy. Further studies are required to validate the use of IL4 and TCRγδ T cells as biomarkers of the different CD forms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/eji.201948098DOI Listing
December 2019

Prevalence of allergy and asthma in a rural community of children and adults in Bolivian Chaco.

Immunol Lett 2019 11 7;215:45-47. Epub 2019 Aug 7.

Department of Experimental and Clinical Medicine, University of Florence, Italy. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.imlet.2019.08.001DOI Listing
November 2019

Biologicals targeting type 2 immunity: Lessons learned from asthma, chronic urticaria and atopic dermatitis.

Eur J Immunol 2019 09 12;49(9):1334-1343. Epub 2019 Aug 12.

Department of Experimental and Clinical Medicine and DENOTHE Center, University of Florence, Florence, Italy.

During the last decades, progression of research has led to great achievements for treatment and therapy of several disabling disorders, particularly in the field of chronic inflammatory diseases. The increased knowledge of the molecular mechanisms operating in such diseases has represented the first step in this process, and the discovery of molecules able to interfere with the natural history of the diseases, has been the second. This review is focused on the effects of biologics on type 2 diseases such as asthma, chronic urticaria and atopic dermatitis, both biologics just approved for clinical application and also those that are currently undergoing clinical trials. We will also discuss aspects and emphasize clinical trials and recently published studies, as well as research that is currently in the progress, which will be highly relevant for basic immunologists. Likewise, we will cover aspects that are pertinent for clinical immunologists and highlight translational studies that are evaluating novel biologicals in animal models.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/eji.201948156DOI Listing
September 2019

The protease systems and their pathogenic role in juvenile idiopathic arthritis.

Autoimmun Rev 2019 Aug 8;18(8):761-766. Epub 2019 Jun 8.

Department of Experimental and Clinical Biomedical Sciences, University of Florence, Italy.

Numerous proteases produced by synovial cells of arthritic joints, chondrocytes, macrophages and polymorphonuclear cells have been identified as responsible for the joint damage in rheumatoid arthritis. There are few scientific contributions aimed to identify similar mechanisms in the joints of patients with juvenile idiopathic arthritis. Recently, some mechanisms emerged, triggered by the TH17 and TH1/TH17 lymphocytes, which could shed new light on unexpected pathogenic pathways of joint damage in the JIA, mainly regarding the RANK-RANKL pathway. Other novelties are linked to the mechanisms of acidification of the synovial fluid, which create a microenvironment suitable for the extracellular activity of lysosomal enzymes. Some biological drugs currently used in the therapy of JIA can interfere with these mechanisms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.autrev.2019.06.010DOI Listing
August 2019

Th17 and Th1 Lymphocytes in Oligoarticular Juvenile Idiopathic Arthritis.

Front Immunol 2019 14;10:450. Epub 2019 Mar 14.

Department of Experimental and Clinical Medicine and DENOTHE Center, University of Florence, Florence, Italy.

In the last years much attention has focused on the Th17 and Th1 phenotypes and on their pathogenic role in juvenile idiopathic arthritis, investigating how the cytokines produced by T helper cells act on resident cells on the synovia and which signal transduction pathways regulate Th17 cells proliferation and plasticity. In this context, an important milestone was represented by the identification of the non-classic Th1 phenotype, developed from the shift of Th17 cells. The cytokine TNF-α, beyond its well-known proinflammatory activity is involved in this process and this is one of the reasons why the TNF-α inhibitors are widely used in the treatment of juvenile idiopathic arthritis patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2019.00450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6428030PMC
June 2020

Omalizumab dampens type 2 inflammation in a group of long-term treated asthma patients and detaches IgE from FcεRI.

Eur J Immunol 2018 12 9;48(12):2005-2014. Epub 2018 Oct 9.

Department of Experimental and Clinical Medicine and DENOTHE Center, University of Florence, Florence, Italy.

Even if omalizumab is broadly used in the treatment of severe, allergic asthma, the immunological effects in long-term treated patients have not been fully elucidated. To this aim, a cohort of 15 allergic asthmatic patients treated with omalizumab for at least three years was compared with 12 allergic asthma patients treated with standard therapy. Omalizumab treated asthmatic patients showed lower frequencies of circulating plasmacytoid DCs, and lower CD154 expression on CD4 T-helper cells than the control group. Moreover, basophils and DCs from omalizumab-treated patients had lower surface expression of IgE compared to the control group. In a longitudinal evaluation of two patients that started omalizumab treatment, we show that FcεRI free of IgE were evident on basophils just after four weeks of drug administration. Finally, in vitro experiments with basophils obtained from healthy donors confirm that omalizumab is able to detach IgE from high affinity IgE receptors. Collectively these data indicate that long-term omalizumab treatment dampens type 2 inflammation acting on different cell types that play a pivotal role in the pathogenesis of allergic asthma. Moreover, we have identified a further mechanism of action of omalizumab, such as the ability to detach IgE from its receptor.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/eji.201847668DOI Listing
December 2018

Eomes controls the development of Th17-derived (non-classic) Th1 cells during chronic inflammation.

Eur J Immunol 2019 01 22;49(1):79-95. Epub 2018 Nov 22.

Department of Experimental and Clinical Medicine and DENOTHE Center, University of Florence, Firenze, Italy.

It is well accepted that Th17 cells are a highly plastic cell subset that can be easily directed toward the Th1 phenotype in vitro and also in vivo during inflammation. However, there is an ongoing debate regarding the reverse plasticity (conversion from Th1 to Th17). We show here that ectopic ROR-γt expression can restore or initiate IL-17 expression by non-classic or classic Th1 cells, respectively, while common pro-Th17 cytokine cocktails are ineffective. This stability of the Th1 phenotype is at least partially due to the presence of a molecular machinery governed by the transcription factor Eomes, which promotes IFN-γ secretion while inhibiting the expression of ROR-γt and IL-17. By using a mouse model of T cell-dependent colitis we demonstrate that Eomes controls non-classic Th1 cell development also in vivo and promotes their pathogenic potential. Eomes expression associates to a highly inflammatory phenotype also in patients with juvenile idiopathic arthritis. Indeed, it favors the acquisition of a cytotoxic signature, and promotes the development of IFN-γ GM-CSF cells that have been described to be pathogenic in chronic inflammatory disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/eji.201847677DOI Listing
January 2019

Therapeutic Efficacy of Autologous Non-Mobilized Enriched Circulating Endothelial Progenitors in Patients With Critical Limb Ischemia - The SCELTA Trial.

Circ J 2018 05 23;82(6):1688-1698. Epub 2018 Mar 23.

Careggi University Hospital.

Background: The therapeutic efficacy of bone marrow mononuclear cells (BM-MNC) autotransplantation in critical limb ischemia (CLI) has been reported. Variable proportions of circulating monocytes express low levels of CD34 (CD14CD34cells) and behave in vitro as endothelial progenitor cells (EPCs). The aim of the present randomized clinical trial was to compare the safety and therapeutic effects of enriched circulating EPCs (ECEPCs) with BM-MNC administration.Methods and Results:ECEPCs (obtained from non-mobilized peripheral blood by immunomagnetic selection of CD14and CD34cells) or BM-MNC were injected into the gastrocnemius of the affected limb in 23 and 17 patients, respectively. After a mean of 25.2±18.6-month follow-up, both groups showed significant and progressive improvement in muscle perfusion (primary endpoint), rest pain, consumption of analgesics, pain-free walking distance, wound healing, quality of life, ankle-brachial index, toe-brachial index, and transcutaneous PO. In ECEPC-treated patients, there was a positive correlation between injected CD14CD34cell counts and the increase in muscle perfusion. The safety profile was comparable between the ECEPC and BM-MNC treatment arms. In both groups, the number of deaths and major amputations was lower compared with eligible untreated patients and historical reference patients.

Conclusions: This study supports previous trials showing the efficacy of BM-MNC autotransplantation in CLI patients and demonstrates comparable therapeutic efficacy between BM-MNC and EPEPCs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1253/circj.CJ-17-0720DOI Listing
May 2018

Guidelines for the use of flow cytometry and cell sorting in immunological studies.

Authors:
Andrea Cossarizza Hyun-Dong Chang Andreas Radbruch Mübeccel Akdis Immanuel Andrä Francesco Annunziato Petra Bacher Vincenzo Barnaba Luca Battistini Wolfgang M Bauer Sabine Baumgart Burkhard Becher Wolfgang Beisker Claudia Berek Alfonso Blanco Giovanna Borsellino Philip E Boulais Ryan R Brinkman Martin Büscher Dirk H Busch Timothy P Bushnell Xuetao Cao Andrea Cavani Pratip K Chattopadhyay Qingyu Cheng Sue Chow Mario Clerici Anne Cooke Antonio Cosma Lorenzo Cosmi Ana Cumano Van Duc Dang Derek Davies Sara De Biasi Genny Del Zotto Silvia Della Bella Paolo Dellabona Günnur Deniz Mark Dessing Andreas Diefenbach James Di Santo Francesco Dieli Andreas Dolf Vera S Donnenberg Thomas Dörner Götz R A Ehrhardt Elmar Endl Pablo Engel Britta Engelhardt Charlotte Esser Bart Everts Anita Dreher Christine S Falk Todd A Fehniger Andrew Filby Simon Fillatreau Marie Follo Irmgard Förster John Foster Gemma A Foulds Paul S Frenette David Galbraith Natalio Garbi Maria Dolores García-Godoy Jens Geginat Kamran Ghoreschi Lara Gibellini Christoph Goettlinger Carl S Goodyear Andrea Gori Jane Grogan Mor Gross Andreas Grützkau Daryl Grummitt Jonas Hahn Quirin Hammer Anja E Hauser David L Haviland David Hedley Guadalupe Herrera Martin Herrmann Falk Hiepe Tristan Holland Pleun Hombrink Jessica P Houston Bimba F Hoyer Bo Huang Christopher A Hunter Anna Iannone Hans-Martin Jäck Beatriz Jávega Stipan Jonjic Kerstin Juelke Steffen Jung Toralf Kaiser Tomas Kalina Baerbel Keller Srijit Khan Deborah Kienhöfer Thomas Kroneis Désirée Kunkel Christian Kurts Pia Kvistborg Joanne Lannigan Olivier Lantz Anis Larbi Salome LeibundGut-Landmann Michael D Leipold Megan K Levings Virginia Litwin Yanling Liu Michael Lohoff Giovanna Lombardi Lilly Lopez Amy Lovett-Racke Erik Lubberts Burkhard Ludewig Enrico Lugli Holden T Maecker Glòria Martrus Giuseppe Matarese Christian Maueröder Mairi McGrath Iain McInnes Henrik E Mei Fritz Melchers Susanne Melzer Dirk Mielenz Kingston Mills David Mirrer Jenny Mjösberg Jonni Moore Barry Moran Alessandro Moretta Lorenzo Moretta Tim R Mosmann Susann Müller Werner Müller Christian Münz Gabriele Multhoff Luis Enrique Munoz Kenneth M Murphy Toshinori Nakayama Milena Nasi Christine Neudörfl John Nolan Sussan Nourshargh José-Enrique O'Connor Wenjun Ouyang Annette Oxenius Raghav Palankar Isabel Panse Pärt Peterson Christian Peth Jordi Petriz Daisy Philips Winfried Pickl Silvia Piconese Marcello Pinti A Graham Pockley Malgorzata Justyna Podolska Carlo Pucillo Sally A Quataert Timothy R D J Radstake Bartek Rajwa Jonathan A Rebhahn Diether Recktenwald Ester B M Remmerswaal Katy Rezvani Laura G Rico J Paul Robinson Chiara Romagnani Anna Rubartelli Beate Ruckert Jürgen Ruland Shimon Sakaguchi Francisco Sala-de-Oyanguren Yvonne Samstag Sharon Sanderson Birgit Sawitzki Alexander Scheffold Matthias Schiemann Frank Schildberg Esther Schimisky Stephan A Schmid Steffen Schmitt Kilian Schober Thomas Schüler Axel Ronald Schulz Ton Schumacher Cristiano Scotta T Vincent Shankey Anat Shemer Anna-Katharina Simon Josef Spidlen Alan M Stall Regina Stark Christina Stehle Merle Stein Tobit Steinmetz Hannes Stockinger Yousuke Takahama Attila Tarnok ZhiGang Tian Gergely Toldi Julia Tornack Elisabetta Traggiai Joe Trotter Henning Ulrich Marlous van der Braber René A W van Lier Marc Veldhoen Salvador Vento-Asturias Paulo Vieira David Voehringer Hans-Dieter Volk Konrad von Volkmann Ari Waisman Rachael Walker Michael D Ward Klaus Warnatz Sarah Warth James V Watson Carsten Watzl Leonie Wegener Annika Wiedemann Jürgen Wienands Gerald Willimsky James Wing Peter Wurst Liping Yu Alice Yue Qianjun Zhang Yi Zhao Susanne Ziegler Jakob Zimmermann

Eur J Immunol 2017 10;47(10):1584-1797

Maurice Müller Laboratories (DKF), Universitätsklinik für Viszerale Chirurgie und Medizin Inselspital, University of Bern, Murtenstrasse, Bern.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/eji.201646632DOI Listing
October 2017

Role of Type 2 Innate Lymphoid Cells in Allergic Diseases.

Curr Allergy Asthma Rep 2017 Sep 11;17(10):66. Epub 2017 Sep 11.

Department of Experimental and Clinical Medicine and DENOTHE Center, University of Florence, 50134, Florence, Italy.

Purpose Of Review: The adaptive immune response orchestrated by type 2 T helper (Th2) lymphocytes, strictly cooperates with the innate response of group 2 innate lymphoid cells (ILC2), in the protection from helminths infection, as well as in the pathogenesis of allergic disease. The aim of this review is to explore the pathogenic role of ILC2 in different type 2-mediated disorders.

Recent Findings: Recent studies have shown that epithelial cell-derived cytokines and their responding cells, ILC2, play a pathogenic role in bronchial asthma, chronic rhinosinusitis, and atopic dermatitis. The growing evidences of the contribution of ILC2 in the induction and maintenance of allergic inflammation in such disease suggest the possibility to target them in therapy. Biological therapies blocking ILC2 activation or neutralizing their effector cytokines are currently under evaluation to be used in patients with type 2-dominated diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11882-017-0735-9DOI Listing
September 2017

Musculin inhibits human T-helper 17 cell response to interleukin 2 by controlling STAT5B activity.

Eur J Immunol 2017 09 6;47(9):1427-1442. Epub 2017 Jul 6.

Department of Experimental and Clinical Medicine and DENOTHE Center, University of Florence, Firenze, Italy.

We recently demonstrated that human T-helper (Th) 17 cells, unlike Th1 cells, do not proliferate in response to T-cell receptor stimulation, mainly because of their reduced capacity to produce and respond to IL-2. In this study, we show that their lower responsiveness to IL-2 is due to the selective expression of Musculin (MSC), a member of the basic helix-loop-helix transcription factors. We show that MSC expression in human Th17 cells is retinoic acid orphan receptor (ROR)γt-dependent, and allows the upregulation of PPP2R2B, a regulatory member of the protein phosphatase 2A (PP2A) enzyme. High PPP2R2B levels in human Th17 cells were responsible for the reduced STAT5B Ser-193 phosphorylation upon IL-2 signalling and, therefore, impaired STAT5B DNA binding and transcriptional activity on IL-2 target genes. PP2A, observed in Th17 cells, controls also STAT3, dephosphorylating Ser727, thus increasing its activity that plays a crucial role in Th17 development and/or maintenance. Thus, our findings identify an additional mechanism responsible for the limited expansion of human Th17 cells, and could provide a further explanation for the rarity of these cells in inflamed tissues.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/eji.201746996DOI Listing
September 2017

Group 2 Innate Lymphoid Cells Are the Earliest Recruiters of Eosinophils in Lungs of Patients with Allergic Asthma.

Am J Respir Crit Care Med 2017 09;196(6):666-668

1 Department of Experimental and Clinical Medicine University of Florence Florence, Italy.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1164/rccm.201704-0799EDDOI Listing
September 2017

Th17 and Treg lymphocytes as cellular biomarkers of disease activity in Granulomatosis with Polyangiitis.

Authors:
Lorenzo Cosmi

Eur J Immunol 2017 04;47(4):633-636

Department of Experimental and Clinical Medicine and DENOTHE Center, University of Florence, Florence, Italy.

Granulomatosis with Polyangiitis (GPA) (formerly known as Wegener's granulomatosis) is a vasculitis of unknown etiology affecting predominantly small- to medium-sized vessels, usually involving the upper and lower respiratory tract and kidneys. Anti-neutrophil cytoplasmic autoantibodies are probably the initial cause of the inflammatory process that leads to the typical necrotizing lesions. In this issue of the European Journal of Immunology, Szczeklik et al. [Eur. J. Immunol. 2017. 47: 724-733] report some interesting findings on the possible involvement of T-cell subsets in the pathogenesis of the disease. This prospective study, performed on a large cohort of patients, identifies Th17 lymphocytes as the possible pathogenic subset of GPA, and Treg cells as the possible suppressors of the inflammatory process. These two subsets in peripheral blood could be used as cellular biomarkers of disease activity, and this would result particularly useful in the follow-up of patients once the immunosuppressive treatment has been initiated.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/eji.201746986DOI Listing
April 2017

Chitinase 3-like-1 is produced by human Th17 cells and correlates with the level of inflammation in juvenile idiopathic arthritis patients.

Clin Mol Allergy 2016 8;14:16. Epub 2016 Nov 8.

Department of Experimental and Clinical Medicine and DENOTHE Center, University of Florence, 50134 Florence, Italy.

Background: CHI3L1 is a chitinase-like protein without enzymatic activity, produced by activated macrophages, chondrocytes, neutrophils. Recent studies on arthritis, asthma, and inflammatory bowel diseases suggest that chitinases are important in inflammatory processes and tissue remodeling, but their production by human T cells, has never been reported.

Methods: A microarray analysis of gene expression profile was performed on Th17 and classic Th1 cell clones and CHI3L1 was found among the up-regulated genes on Th17 cells. Different types of helper T cell clones (TCCs) were then evaluated by Real Time PCR (RT-PCR) for CHI3L1 mRNA expression; protein expression was investigated in cell lysates by western blotting and in cultures supernatants by ELISA. ELISA was also used to measure CHI3L1 in the serum and in the synovial fluid (SF) of juvenile idiopathic arthritis (JIA) patients.

Results: At mRNA level CHI3L1 was highly expressed by Th17, Th17/Th1, non classic Th1 and even in Th17/Th2 cell clones, whereas it was virtually absent in CD161- classic Th1 and Th2 TCCs. CHI3L1 was also detected in cell culture supernatants of Th17 and Th17-derived cells but not of classic Th1. Moreover CHI3L1 was higher in the SF than in serum of JIA patients, and it positively correlated with the frequency of Th17 and non-classic Th1 cells in SF. CHI3L1 in SF also positively correlated with the C reactive protein (CRP) serum levels, and with the levels of some proinflammatory cytokines, such as IL-6 and p40, which is the common subunit of IL12 and IL23.

Conclusions: Here we describe for the first time CHI3L1 production by T cells owing the Th17 family. Moreover the positive correlation found between the frequency of Th17 and Th17-derived cell subsets and CHI3L1 levels in SF of JIA patients, in agreement with the suggested role of these cells in inflammatory process, candidates CHI3L1 as a possible biological target in JIA treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12948-016-0053-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5100333PMC
November 2016

Immunosuppressive Activity of Abatacept on Circulating T Helper Lymphocytes from Juvenile Idiopathic Arthritis Patients.

Int Arch Allergy Immunol 2016 8;171(1):45-53. Epub 2016 Nov 8.

Department of Experimental and Clinical Medicine and DENOTHE Center, University of Florence, Florence, Italy.

Background: Abatacept is used in the treatment of juvenile idiopathic arthritis (JIA) patients, but the activity of the drug on T helper cell function is not yet fully known.

Methods: The ability of abatacept to affect cytokine production in vitro and the proliferative response to both recall antigens and polyclonal stimulation was firstly assessed in healthy donors. Then, 10 JIA patients who were due to start abatacept treatment were recruited and longitudinally evaluated during the first 90 days of therapy. Both their clinical response to the treatment and in vitro analysis aimed to assess the proliferative response to recall antigens and the proportions of circulating T helper subsets.

Results: Abatacept reduced the proliferative response to recall antigens and the production of proinflammatory cytokines such as IFN-γ and TNF-α in healthy donors in vitro. It was also efficient in improving symptoms and reducing parameters of inflammation in JIA patients. Abatacept reduced the proliferative response to recall antigens, and this effect was significant soon after drug infusion (2 days). Regarding the proportions of circulating CD4+ T lymphocytes, only a reduction in the frequencies of circulating Treg cells was observed.

Conclusions: Abatacept in vitro inhibits proliferation and cytokine production in healthy donors, and reduces parameters of inflammation in vivo in JIA patients. The reduction of the proliferative response to recall antigens induced by abatacept was evident only soon after drug administration, suggesting that its immunosuppressive activity is maintained only for a short time.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000450948DOI Listing
February 2017