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Coexpression of CD163 and CD141 identifies human circulating IL-10-producing dendritic cells (DC-10)

Cellular & Molecular Immunology 2020年第1期17卷 95-107页

作者： Michela Comi Daniele Avancini Francesca santoni de Sio Matteo Villa Molly Javier Uyeda Matteo Floris Daniela Tomasoni Alessandro Bulfone Maria Grazia Roncarolo Silvia Gregori san raffaele telethon institute for gene therapy(SR-TIGET) San Raffaele Scientific Institute(IRCCS)MilanItaly PhD Program in Translational and Molecular Medicine(DIMET) University of Milan-BicoccaMilanItaly Division of Stem Cell Transplantation and Regenerative Medicine Department of PediatricsISCBRMStanford School of MedicineStanfordCAUSA CRS4 Technology Park PolarisPulaItaly

Tolerogenic dendritic cells(DCs)are key players in maintaining immunological homeostasis,dampening immune responses,and promoting ***-10,a tolerogenic population of human IL-10-producing DCs characterized by the expression of HLA-G and ILT4,play a pivotal role in promoting tolerance via T regulatory type 1(Tr1)*** far,the absence of markers that uniquely identify DC-10 has limited in vivo *** in vitro gene expression profiling of differentiated human DCs,we identified CD141 and CD163 as surface markers for *** coexpression of CD141 and CD163 in combination with CD14 and CD16 enables the ex vivo isolation of DC-10 from the peripheral ***14+CD16+CD141+CD163+cells isolated from the peripheral blood of healthy subjects(ex vivo DC-10)produced spontaneously and upon activation of IL-10 and limited levels of ***,in vitro stimulation of allogeneic naive CD4+T cells with ex vivo DC-10 induced the differentiation of alloantigen-specific CD49b+LAG-3+Tr1 ***,ex vivo DC-10 and in vitro generated DC-10 exhibited a similar transcriptional profile,which are characterized by an anti-inflammatory and pro-tolerogenic *** results provide new insights into the phenotype and molecular signature of DC-10 and highlight the tolerogenic properties of circulating *** findings open the opportunity to track DC-10 in vivo and to define their role in physiological and pathological settings.

关键词： Dendritic cells IL-10 T regulatory type 1(Tr1)cells Tolerance

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Is acute recurrent pancreatitis a chronic disease?

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World Journal of Gastroenterology 2008年第7期14卷 995-998页

作者： Alberto Mariani Pier Alberto Testoni Division of Gastroen-terology & Gastrointestinal Endoscopy Vita-Salute San Raffaele University-Scientific Institute San RaffaeleMilanItaly

Whether acute recurrent pancreatitis is a chronic disease is still debated and a consensus is not still reached as demonstrated by differences in the classification of acute recurrent pancreatitis. There is major evidence for considering alcoholic pancreatitis as a chronic disease ab initio while chronic pancreatitis lesions detectable in biliary acute recurrent pancreatitis (ARP) seem a casual association. Cystic fibrosis transmembrane con-ductance regulator (CFTR) gene mutation, hereditary and obstructive pancreatitis seem an acute disease that progress to chronic pancreatitis, likely as a consequence of the activation and proliferation of pancreatic stellate cells that produce and activate collagen and therefore fibrosis. From the diagnostic point of view, in patients with acute recurrent pancreatitis Endoscopic ultrasound (EUS) seems the more reliable technique for an accurate evaluation and follow-up of some ductal and parenchymal abnormalities suspected for early chronic pancreatitis.

关键词： Classification of pancreatitis Acute recurrent pancreatitis Chronic pancreatitis Alcoholic pancreatitis Pancreatic stellate cells

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PTPN22 and islet-specific autoimmunity:What have the mouse models taught us?

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World Journal of Diabetes 2017年第7期8卷 330-336页

作者： Giuseppe Galvani Georgia Fousteri Diabetes Research institute IRCCS San Raffaele Scientific Institute20132 MilanItaly

An allelic variant of the protein tyrosin phosphatase non-receptor 22(PTPN22) gene, PTPN22 R620 W, constitutes the strongest non-HLA genetic risk factor for the development of type 1 diabetes(T1D). A numberstudies using mouse models have addressed how PTPN22 predisposes to T1D. PTPN22 downmodulation, overexpression or expression of the variant gene in genetically manipulated mice has generated controversial results. These discrepancies probably derive from the fact that PTPN22 has differential effects on innate and adaptive immune responses. Moreover, the effects of PTPN22 are dependent on other genetic variables. Here we discuss these findings and try to explain the discrepancies. Exploring the mechanism by which PTPN22 contributes to islet-specific autoimmunity could help us understand its role in T1D pathogenesis and exploit it as a potential therapeutic target to prevent the disease.

关键词： Protein tyrosin phosphatase non-receptor 22 Type 1 diabetes genetic susceptibility Mouse model Autoimmunity Islet-specific autoimmunity

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Tumors and new endoscopic ultrasound-guided therapies

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World Journal of Gastrointestinal Endoscopy 2013年第4期5卷 141-147页

作者： Silvia Carrara Maria Chiara Petrone Pier Alberto Testoni Paolo Giorgio Arcidiacono Scientific institute san raffaele Vita-Salute San Raffaele University

With the advent of linear echoendoscopes, endoscopic ultrasound (EUS) has become more operative and a new field of oncological application has been opened up. From tumor staging to tissue acquisition under EUS-guided fine-needle aspiration, new operative procedures have been developed on the principle of the EUS-guided puncture. A hybrid probe combining radiofrequency with cryotechnology is now available, to be passed through the operative channel of the echoendoscope into the tumor to create an area of ablation. EUS-guided fine-needle injection is emerging as a method to deliver anti-tumoral agents inside the tumor. Ethanol lavage, with or without paclitaxel, has been proposed for the treatment of cystic tumors in non-resectable cases and complete resolution has been recorded in up to 70%-80%. Many other chemical or biological agents have been investigated for the treatment of pancreatic adenocarcinoma: activated allogenic lymphocyte culture (Cytoimplant), a replication-deficient adenovirus vector carrying the tumor necrosis factor-α gene, or an oncolytic attenuated adenovirus (ONYX-015). The potential advantage of treatment under EUS control is the real-time imaging guidance into a deep target likethe pancreas which is extremely difficult to reach by a percutaneous approach. To date there are no randomized controlled trials to confirm the real clinical benefits of these treatments compared to standard therapy so it seems wise to reserve them only for experimental protocols approved by ethics committees.

关键词： Endoscopic ultrasound Pancreatic cancer Endoscopic ultrasound guided ablation Alcohol injection Anti-tumoral injection

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Initial failures of anti-tau antibodies in Alzheimer’s disease are reminiscent of the amyloid-βstory

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Neural Regeneration Research 2023年第1期18卷 117-118页

作者： Bruno P.Imbimbo Claudia Balducci Stefania Ippati Mark Watling Department of Research&Development Chiesi FarmaceuticiParmaItaly Department of Neuroscience Istituto di Ricerche Farmacologiche“Mario Negri”IRCCSMilanItaly san raffaele Scientific institute San Raffaele HospitalMilanItaly CNS&Pain Department TranScrip Ltd.ReadingUK

Tau is an important protein of the central nervous system formed by 352-441 amino acids and encoded by the MAPT(microtubule-associated protein tau)gene on chromosome 17 which generates 6 *** is located in axons,dendrites,nucleus,cell membrane,and synapses of *** protein is also expressed to a lesser extent in astrocytes and oligodendrocytes,although its role in these cells has been little *** protein is also present in the interstitial fluid and can cross into the cerebrospinal fluid(CSF)and reach the systemic circulation.

关键词： tau Alzheimer cerebrospinal

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Wilson's disease: Prospective developments towards new therapies

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World Journal of Gastroenterology 2017年第30期23卷 5451-5456页

作者： Giusy Ranucci Roman Polishchuck raffaele Iorio Department of Translational Medical Science Section of Pediatric University Federico Ⅱ telethon institute of genetics and Medicine

Wilson's disease(WD) is an autosomal recessive disorder of copper metabolism, caused by mutations in the ATP7 B gene. A clear demand for novel WD treatment strategies has emerged. Although therapies using zinc salts and copper chelators can effectively cure WD, these drugs exhibit limitations in a substantial pool of WD patients who develop intolerance and/or severe side effects. Several lines of research have indicated intriguing potential for novel strategies and targets for development of new therapies. Here, we review these new approaches, which comprise correction of ATP7 B mutants and discovery of new compounds that circumvent ATP7B-deficiency, as well as cell and gene therapies. We also discuss whether and when these new therapeutic strategies will be translated into clinical use, according to the key requirements for clinical trials that remain to be met. Finally, we discuss the hope for the current rapidly developing research on molecular mechanisms underlying WD pathogenesis and for the related potential therapeutic targets to provide a solid foundation for the next generation of WD therapies that may lead to an effective, tolerable and safe cure.

关键词： ATP7B Stem cell-derived hepatocyte like cells Methanobactin Heat shock protein 70 p38 JNK Correctors Translational medicine Precision medicine

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Lentiviral haematopoietic stem-cell gene therapy for early-onset metachromatic leukodystrophy:long-term results from a non-randomised,open-label,phase 1/2 trial and expanded access

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四川生理科学杂志 2021年第11期43卷 2002-2002页

作者： Francesca Fumagalli san raffaele telethon institute for gene therapy (SR-Tiget) IRCCS San Raffaele Scientific Institute Milan Italy Pediatric Immunohematology Unit and BMT Program IRCCS San Raffaele Scientific Institute Milan Italy Units of Neurology and Neurophysiology IRCCS San Raffaele Scientific Institute Milan Italy Department of Neurology ASST Papa Giovanni XXIII Bergamo Italy Neuroradiology Unit IRCCS San Raffaele Scientific Institute Milan Italy University Centre of Statistics in the Biomedical Sciences (CUSSB) Milan Italy Vita-Salute san raffaele University Milan Italy

Background:Effective treatment for metachromatic leukodystrophy(MLD)remains a substantial unmet medical *** this study we investigated the safety and efficacy of atidarsagene autotemcel(arsa-cel)in patients with ***:This study is an integrated analysis of results from a prospective,non-randomised,phase 1/2 clinical study and expanded-access frameworks.29 paediatric patients with pre-symptomatic or early-symptomatic early-onset MLD with biochemical and molecular confirmation of diagnosis were treated with arsa-cel,a gene therapy containing an autologous haematopoietic stem and progenitor cell(HSPC)population transduced ex vivo with a lentiviral vector encoding human arylsulfatase A(ARSA)cDNA.

关键词： dystrophy diagnosis expanded

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ISWI ATP-dependent remodeling of nucleoplasmic u-speckles in the brain of Drosophila melanogaster

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Journal of genetics and Genomics 2017年第2期44卷 85-94页

作者： Luca Lo Piccolo Andrea Attardi Rosa Bonaccorso Lorenzo Li Greci Giorgio Giurato Antonia Maria Rita Ingrassia Maria Cristina Onorati STEBICEF Department University of Palermo Kyoto institute of Technology Neuroimmunology Unit of san raffaele Hospital Turku Center for Biotechnology University of Turku Genomix4Life Srl University of Salerno Baronissi Campus

Heterogeneous nuclear ribonucleoproteins（hn RNPs） belong to the RNA-binding proteins family. They are involved in processing heterogeneous nuclear RNAs（hn RNAs） into mature m RNAs. These proteins participate in every step of m RNA cycle, such as m RNA export, localization, translation, stability and alternative splicing. At least 14 major hn RNPs, which have structural and functional homologues in mammals, are expressed in Drosophila melanogaster. Until now, six of these hn RNPs are known to be nucleus-localized and associated with the long non-coding RNA（lnc RNA） heat shock responsive u（hsru）in the omega speckle compartments（u-speckles）. The chromatin remodeler ISWI is the catalytic subunit of several ATP-dependent chromatin-remodeling complexes, and it is an essential factor for organization of u-speckles. Indeed, in ISWI null mutant, severe defects in u-speckles structure are detectable. Here, we clarify the role of ISWI in the hn RNPs-hsru interaction. Moreover, we describe how ISWI by its remodeling activity, controls hsru and hn RNPs engagement in u-speckles. Finally, we demonstrate that the sequestration of hn RNPs in u-speckles nuclear compartment is a fundamental event in gene expression control and represents a key step in the regulation of several pathways.

关键词： Omega speckles hnRNPs lncRNA Nuclear body Chromatin remodelers

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LIM-domain-only 4(LMO4)enhances CD8^(+)T-cell stemness and tumor rejection by boosting IL-21-STAT3 signaling

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Signal Transduction and Targeted therapy 2024年第9期9卷 4066-4078页

作者： Roland C.Schelker Jessica Fioravanti Fabio Mastrogiovanni Jeremy G.Baldwin Nisha Rana Peng Li Ping Chen Timea Vadász Rosanne Spolski Christoph Heuser-Loy Dragana Slavkovic-Lukic Pedro Noronha Giuseppe Damiano Laura Raccosta Daniela Maggioni Sree Pullugula Jian-Xin Lin Jangsuk Oh Patrick Grandinetti Mario Lecce Leo Hesse Emilia Kocks Azucena Martín-santos Claudia Gebhard William G.Telford Yun Ji Nicholas P.Restifo Vincenzo Russo Michael Rehli Wolfgang Herr Warren J.Leonard Luca Gattinoni Division of Functional Immune Cell Modulation Leibniz Institute for ImmunotherapyRegensburgGermany Center for Cancer Research National Cancer InstituteNational Institutes of HealthBethesdaMDUSA Laboratory of Molecular Immunology and the Immunology Center National HeartLung and Blood InstituteNational Institutes of HealthBethesdaMDUSA Department of Internal MedicineⅢ University Hospital RegensburgRegensburgGermany Next generation Sequencing Core Leibniz Institute for ImmunotherapyRegensburgGermany Immuno-Biotherapy of Melanoma and Solid Tumors Unit Division of Experimental OncologyIRCCS Scientific Institute San RaffaeleMilanItaly Vita-Salute san raffaele University MilanItaly University of Regensburg RegensburgGermany National Center for Tumor Diseases WERA SiteWürzburg-Erlangen-Regensburg-AugsburgGermany Center for Immunomedicine in Transplantation and Oncology University Hospital RegensburgRegensburgGermany

High frequencies of stem-like memory T cells in infusion products correlate with superior patient outcomes across multiple T cell therapy ***,we analyzed a published CRISPR activation screening to identify transcriptional regulators that could be harnessed to augment stem-like behavior in CD8^(+)T *** IFN-γproduction as a proxy for CD8^(+)T cell terminal differentiation,LMO4 emerged among the top hits inhibiting the development of effectors ***,we found that Lmo4 was downregulated upon CD8^(+)T cell activation but maintained under culture conditions facilitating the formation of stem-like T *** employing a synthetic biology approach to ectopically express LMO4 in antitumor CD8^(+)T cells,we enabled selective expansion and enhanced persistence of transduced cells,while limiting their terminal differentiation and ***4 overexpression promoted transcriptional programs regulating stemness,increasing the numbers of stem-like CD8^(+)memory T cells and enhancing their polyfunctionality and recall *** tested in syngeneic and xenograft tumor models,LMO4 overexpression boosted CD8^(+)T cell antitumor immunity,resulting in enhanced tumor *** than directly modulating gene transcription,LMO4 bound to JAK1 and potentiated STAT3 signaling in response to IL-21,inducing the expression of target genes(Tcf7,Socs3,Junb,and Zfp36)crucial for memory ***/Cas9-deletion of Stat3 nullified the enhanced memory signature conferred by LMO4,thereby abrogating the therapeutic benefit of LMO4 *** results establish LMO4 overexpression as an effective strategy to boost CD8^(+)T cell stemness,providing a new synthetic biology tool to bolster the efficacy of T cell-based immunotherapies.

关键词： STAT3 immunity LMO4

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Genomic and functional evaluation of TNFSF14 in multiple sclerosis susceptibility

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Journal of genetics and Genomics 2021年第6期48卷 497-507页

作者： Miriam Zuccala Nadia Barizzone Elena Boggio Luca Gigliotti Melissa Sorosina Chiara Basagni Roberta Bordoni Ferdinando Clarelli santosh Anand Eleonora Mangano Domizia Vecchio Elena Corsetti Serena Martire Simona Perga Daniela Ferrante Alberto Gajofatto Andrei Ivashynka Claudio Solaro Roberto Cantello Vittorio Martinelli Giancarlo Comi Massimo Filippi Federica Esposito Maurizio Leone Gianluca De Beilis Umberto Dianzani Filippo Martinelli-Boneschi sandra D’Alfonso Department of Health Sciences Center on Autoimmune and Allergic Diseases(CAAD)UPOUniversity of Eastern PiedmontA.AvogadroNovara 28100Italy Consorzio Interuniversitario di Biotecnologie(CIB) Trieste 34149Italy Laboratory of Human genetics of Neurological Disorders Institute of Experimental NeurologyDivision of NeurosciencesIRCCS San Raffaele Scientific InstituteMilan 20132Italy National Research Council of Italy Institute for Biomedical TechnologiesSegrateMilan 20090Italy Department of genetic Medicine and Development(GEDEV) Faculty of MedicineUniversity of Geneva Medical SchoolGeneva 1211Switzerland Department of Informatics Systems and Communications(DISCo)University of Milano-BicoccaMilan 20126Italy MS Centre SCDU NeurologyAOU Maggiore della CaritàNovara 28100Italy Department of Translational Medicine Interdisciplinary Research Center of Autoimmune Diseases(IRCAD)University of Eastern PiedmontNovaraAvogadro UniversityNovara 28100Italy Neuroscience institute Cavalieri Ottolenghi OrbassanoTurin 10043Italy Neurobiology Unit Neurology-CReSM(Regional Referring Center of Multiple Sclerosis)AOU San Luigi GonzagaOrbassanoTurin 10043Italy Department of Neuroscience‘Rita Levi Montalcini’ University of TurinTurin 10126Italy Department of Neuroscience Biomedicine and Movement SciencesUniversity of VeronaVerona 37134Italy UO Neurologia Fondazione IRCCS Casa Sollievo della Sofferenza San Giovanni RotondoFoggia 71013Italy Centro Recupero e Rieducazione Funzionale“Mons L Novarese” Moncrivello(VC)13040Italy Department of Neurology IRCCS San Raffaele Scientific InstituteMilan 20132Italy Neuroimaging Research Unit Institute of Experimental NeurologyDivision of NeuroscienceIRCCS San Raffaele Scientific InstituteMilan 20132Italy Vita-Salute san raffaele University Milan 20138Italy Neurophysiology Unit IRCCS San Raffaele Scientific InstituteMilan 20138Italy Dino Ferrari Centre Neuroscience SectionDepartment of Pathophysiology and Transplantation(DEPT)University of MilanMilan 20122

Among multiple sclerosis(MS)susceptibility genes,the strongest non-human leukocyte antigen(HLA)signal in the Italian population maps to the TNFSF14 gene encoding LIGHT,a glycoprotein involved in dendritic cell(DC)*** fine-mapping in a large Italian dataset(4,198 patients with MS and3,903 controls),we show that the TNFSF14 intronic SNP rs1077667 is the primarily MS-associated variant in the *** quantitative trait locus(e QTL)analysis indicates that the MS risk allele is significantly associated with reduced TNFSF14 messenger RNA levels in blood cells,which is consistent with the allelic imbalance in RNA-Seq reads(Pgene expression(Pgenesis.

关键词： Multiple sclerosis TNFSF14 LIGHT Fine-mapping analysis SNV

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