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Neuro faces of beneficial T cells:essential in brain,impaired in aging and neurological diseases,and activated functionally by neurotransmitters and neuropeptides

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Neural Regeneration Research 2023年第6期18卷 1165-1178页

作者： Mia Levite Faculty of Medicine The Hebrew University of JerusalemCampus Ein KaremJerusalemIsrael Institute of Gene Therapy The Hadassah University Hospital-Ein KaremJerusalemIsrael

T cells are essential for a healthy life,performing continuously:immune surveillance,recognition,protection,activation,suppression,assistance,eradication,secretion,adhesion,migration,homing,communications,and additional tasks.This paper describes five aspects of normal beneficial T cells in the healthy or diseased brain.First,normal beneficial T cells are essential for normal healthy brain functions:cognition,spatial learning,memory,adult neurogenesis,and neuroprotection.T cells decrease secondary neuronal degeneration,increase neuronal survival after central nervous system(CNS) injury,and limit CNS inflammation and damage upon injury and infection.Second,while pathogenic T cells contribute to CNS disorders,recent studies,mostly in animal models,show that specific subpopulations of normal beneficial T cells have protective and regenerative effects in seve ral neuroinflammatory and neurodegenerative diseases.These include M ultiple Sclerosis(MS),Alzheimer’s disease,Parkinson’s disease,Amyotrophic Lateral Sclerosis(ALS),stro ke,CNS trauma,chronic pain,and others.Both T cell-secreted molecules and direct cell-cell contacts deliver T cell neuroprotective,neuro regenerative and immunomodulato ry effects.Third,normal beneficial T cells are abnormal,impaired,and dysfunctional in aging and multiple neurological diseases.Different T cell impairments are evident in aging,brain tumors(mainly Glioblastoma),seve re viral infections(including COVID-19),chro nic stress,major depression,schizophrenia,Parkinson’s disease,Alzheimer’s disease,ALS,MS,stro ke,and other neuro-pathologies.The main detrimental mechanisms that impair T cell function are activation-induced cell death,exhaustion,senescence,and impaired T cell stemness.Fo urth,several physiological neurotransmitters and neuro peptides induce by themselves multiple direct,potent,beneficial,and therapeutically-relevant effects on normal human T cells,via their receptors in T cells.This scientific field is called "Nerve-Driven Immunity".The main neurotransmitters and neuropept

关键词： aging dopamine glutamate nerve-driven immunity neurological diseases neuropeptides neurotransmitters Personalized Adoptive Neuro-Immunotherapy T cells

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Evaluation of direct intramural injection to the bladder wall as a method for developing orthotopic tumor models

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Animal Models and Experimental Medicine 2022年第6期5卷 575-581页

作者： Masoud Bitaraf Samad Muhammadnejad Ashkan Azimzadeh Saman Behboodi Tanourlouee Erfan Amini Masoumeh Majidi Zolbin Abdol-Mohammad Kajbafzadeh Pediatric Urology and Regenerative Medicine Research Center GeneCell and Tissue Research InstituteTehran University of Medical SciencesTehranIran gene therapy Research Center Digestive Diseases Research InstituteTehran University of Medical SciencesTehranIran Uro-oncology Research Center Tehran University of Medical SciencesTehranIran

Background:Bladder cancer poses a great burden on society and its high rate of recurrence and treatment failure necessitates use of appropriate animal models to study its pathogenesis and test novel treatments.Orthotopic models are superior to other types since they provide a normal microenvironment.Four methods are described for developing bladder cancer models inside the animal’s bladder.Direct intramural injection is one of these methods and is widely used.However,its efficacy in model development has not yet been studied.We aimed to evaluate the efficacy and success rate of the direct intramural injection method of developing an orthotopic model for the study of bladder cancer.Method:Tumor cell lines were prepared in four microtubes.Aliquots of 200×10^(3) cells were injected through a 27 gauge needle into the ventral wall of the bladders of 4male and 4 female BALB/c mice following a midline 1 cm laparotomy incision.In addition,1 million cells from each microtube were injected into the flanks of control mice.To prevent infection and alleviate pain,5 mg/kg enrofloxacin and 2.5 mg/kg flunixin meglumine,respectively,were injected subcutaneously.Results:Tumors formed in all mice,resulting in 100% take rate and zero post-operation mortality.Surgery time was≤15 min per mouse.In two mice,tumors were found in the peritoneal space as well.Conclusion:Direct intramural injection is a rapid,reliable,and reproducible method for developing orthotopic models of bladder cancer.It can be done on both male and female mice and only requires readily available surgical tools.However,needle track can result in cell spillage and peritoneal tumors.

关键词： animal model bladder cancer bladder wall injection model evaluation orthotopic model

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New gene therapy strategies for hepatic fibrosis

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World Journal of Gastroenterology 2015年第13期21卷 3813-3825页

作者： Adriana M Salazar-Montes Luis D Hernández-Ortega Martha S Lucano-Landeros Juan Armendariz-Borunda Department of Molecular Biology and Genomics Institute for Molecular Biology and Gene TherapyUniversity of GuadalajaraGuadalajaraJalisco 44281México

The liver is the largest internal organ of the body, which may suffer acute or chronic injury induced by many factors, leading to cirrhosis and hepatocarcinoma. Cirrhosis is the irreversible end result of fibrous scarring and hepatocellular regeneration, characterized by diffuse disorganization of the normal hepatic structure, regenerative nodules and fibrotic tissue. Cirrhosis is associated with a high co-morbidity and mortality without effective treatment, and much research has been aimed at developing new therapeutic strategies to guarantee recovery. Liver-based gene therapy has been used to downregulate specific genes, to block the expression of deleterious genes, to delivery therapeutic genes, to prevent allograft rejection and to augment liver regeneration. Viral and non-viral vectors have been used, with viral vectors proving to be more efficient. This review provides an overview of the main strategies used in liver-gene therapy represented by non-viral vectors, viral vectors, novel administration methods like hydrodynamic injection, hybrids of two viral vectors and blocking molecules, with the hope of translating findings from the laboratory to the patient′s bed-side.

关键词： gene therapy Hepatic fibrosis Viral vectors Non-vi

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Targeting copper to combat macrophage-driven inflammation: a potential advanced therapeutic strategy

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Signal Transduction and Targeted therapy 2023年第10期8卷 4426-4427页

作者： Ralf Weiskirchen institute of Molecular Pathobiochemistry Experimental Gene Therapy and Clinical Chemistry(IFMPEGKC)RWTH University Hospital AachenPauwelsstr.30D-52074AachenGermany

In a recent paper published in Nature,Solier and coworkers showed that a rationally designed dimer of metformin targeting mitochondrial copper content can effectively oppose macrophage activation and plasticity.1 Since macrophages play critical roles in the initiation and maintenance of inflammation,this drug termed supformin holds promise to be a therapeutic effective in suppressing inflammation-related diseases related to macrophages.

关键词： inflammation therapeutic macrophage

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用合成免疫学打开肿瘤免疫治疗的瓶颈(英文)

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Science Bulletin 2015年第11期60卷 977-985,I0007页

作者：陈志英马飞黄海亮何成宜 Laboratory for gene and Cell therapy Chinese Academy of Sciences Shenzhen Institute of Advanced Technology Analytic and Translational genetics Unit Massachusetts General Hospital Broad institute of Massachusetts institute of Technology and Harvard University

近年来,肿瘤免疫治疗取得了令人瞩目的重大突破,采用过继免疫技术输入工程抗体或工程效应T细胞,一些接受治疗的患者获得持久的缓解甚至痊愈.然而,这些单靶点治疗技术对部分患者没有疗效.有证据表明,肿瘤的异质性(heterogeneity)和不断进... 详细信息

近年来,肿瘤免疫治疗取得了令人瞩目的重大突破,采用过继免疫技术输入工程抗体或工程效应T细胞,一些接受治疗的患者获得持久的缓解甚至痊愈.然而,这些单靶点治疗技术对部分患者没有疗效.有证据表明,肿瘤的异质性(heterogeneity)和不断进化(evolving)的特性是造成治疗失败的原因,只有发展出针对这些肿瘤特性的新方法,才能实现新的突破.本文提出用合成免疫策略(synthetic immunity,SI)来实现这一目标.SI的原则是通过制备一组工程抗体和抗体重新定向的细胞毒T淋巴细胞(antibody-retargeted cytotoxic T cells)高度特异性地杀死全部肿瘤细胞系而达到根治的目的.要实现这一目标,只能通过系统化方法来选择组合工程抗体,具体是建立一个肿瘤抗原系统树(tumor epitope-tree)来确定肿瘤细胞系及其抗原的系统构成,然后选择"树干或主要分杈"上的"抗原靶点组"来进行过继免疫治疗,最终消灭所有肿瘤细胞系.同时结合其他技术如扩大抗原表位数量、提高抗体亲和力和T细胞活性等,可以进一步提高SI的效率.此外,用非病毒DNA基因载体在体内生产工程抗体将是一个安全、有效和经济的解决方案.

关键词：免疫治疗抗肿瘤治疗效果抗体生成抗原表位出租车免疫疗法诱导免疫

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Distribution and effects of polymorphic RANTES gene alleles in HIV/HCV coinfection - A prospective cross-sectional study

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World Journal of Gastroenterology 2005年第48期11卷 7631-7638页

作者： Golo Ahlenstiel Agathe Iwan Jacob Nattermann Karin Bueren Jürgen K Rockstroh Hans H Brackmann Bernd Kupfer Olfert Landt Amnon Peled Tilman Sauerbruch Ulrich Spengler Rainer P Woitas Department of Internal Medicine 1 institute of Experimental Hematology institute of Medical Microbiology and Immunology TIB MOLBIOL Synthesis Laboratory Goldyne Savad Institute of Gene Therapy

AIM: Chemokines and their receptors are crucial for immune responses in HCV and HIV infection. RANTES gene polymorphisms lead to altered gene expression and influence the natural course of HIV infection. Therefore,these mutations may also affect the course of HIV/HCV coinfection.METHODS: We determined allele frequencies of RANTES-403 (G→A), RANTES-28 (C→G) and RANTESIN1.1 (T→C) polymorphisms using real-time PCR and hybridization probes in patients with HIV (n = 85), HCV (n= 112), HIV/HCV coinfection (n = 121), and 109 healthy controls. Furthermore, HIV and HCV loads as well as CD4+ and CD8+ cell counts were compared between different RANTES genotypes.RESULTS: Frequencies of RANTES-403 A, RANTES-28 G and RANTES-IN1.1 C alleles were higher in HIV infected patients than in healthy controls (-403: 28.2% vs 15.1%,P = 0.002; -28: 5.4% vs 2.8%, not significant; IN1.1:19.0% vs 11.0%, P = 0.038). In HIV/HCV coinfected patients, these RANTES alleles were less frequent than in patients with HIV infection alone (15.4% P = 0.002;1.7%; P = 0.048; 12.0%; not significant). Frequencies of these alleles were not significantly different between HIV/HCV positive patients, HCV positive patients and healthy controls.CONCLUSION: All three RANTES polymorphisms showed increased frequencies of the variant allele exclusively in patients with HIV monoinfection. The finding that the frequencies of these alleles remained unaltered in HIV/HCV coinfected patients suggests that HCV coinfection interferes with selection processes associated with these alleles in HIV infection.

关键词： RANTES 基因多态性爱滋病丙型肝炎病毒

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Mesenchymal stem cells and the neuronal microenvironment in the area of spinal cord injury

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Neural Regeneration Research 2019年第2期14卷 227-237页

作者： Yana O.Mukhamedshina Olga A.Gracheva Dina M.Mukhutdinova Yurii A.Chelyshev Albert A.Rizvanov OpenLab gene and Cell Technologies Institute of Fundamental Medicine and Biology Kazan (Volga Region)Federal University Department of Histology Cytology and Embryology Kazan State Medical University Department of therapy and Clinical Diagnostics with radiology Faculty of Veterinary Medicine Bauman Kazan State Academy of Veterinary Medicine OpenLab gene and Cell Technologies Institute of Fundamental Medicine and Biology Kazan (Volga Region) Federal University

Cell-based technologies are used as a therapeutic strategy in spinal cord injury(SCI). Mesenchymal stem cells(MSCs), which secrete various neurotrophic factors and cytokines, have immunomodulatory, anti-apoptotic and anti-inflammatory effects, modulate reactivity/phenotype of astrocytes and the microglia, thereby promoting neuroregeneration seem to be the most promising. The therapeutic effect of MSCs is due to a paracrine mechanism of their action, therefore the survival of MSCs and their secretory phenotype is of particular importance. Nevertheless, these data are not always reported in efficacy studies of MSC therapy in SCI. Here, we provide a review with summaries of preclinical trials data evaluating the efficacy of MSCs in animal models of SCI. Based on the data collected, we have tried(1) to establish the behavior of MSCs after transplantation in SCI with an evaluation of cell survival, migration potential, distribution in the area of injured and intact tissue and possible differentiation;(2) to determine the effects MSCs on neuronal microenvironment and correlate them with the efficacy of functional recovery in SCI;(3) to ascertain the conditions under which MSCs demonstrate their best survival and greatest efficacy.

关键词： spinal cord injury mesenchymal stem cells survival migration Rho/ROCK/PTEN astrocytes microglia myelin-forming cells axon growth tissue integrity

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Stem cell-based therapy for human diseases

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Signal Transduction and Targeted therapy 2022年第9期7卷 3242-3282页

作者： Duc M.Hoang Phuong T.Pham Trung Q.Bach Anh T.L.Ngo Quyen T.Nguyen Trang T.K.Phan Giang H.Nguyen Phuong T.T.Le Van T.Hoang Nicholas R.Forsyth Michael Heke Liem Thanh Nguyen Department of Research and Development Vinmec Research Institute of Stem Cell and Gene TechnologyVinmec Healthcare SystemHanoiVietnam Department of Cellular therapy Vinmec High.Tech CenterVinmec Healthcare SsystemHanoiVietnam institute for Science&Technology in Medicine Keele UniversityKeeleUK a Department of Biology Stanford UniversityStanfordCAUSA

Recent advancements in stem cell technology open a new door for patients suffering from diseases and disorders that have yet to be treated.Stem cell-based therapy,including human pluripotent stem cells(hPsCs)and multipotent mesenchymal stem cells(MSCs),has recently emerged as a key player in regenerative medicine.hPSCs are defined as self-renewable cell types conferring the ability to differentiate into various cellular phenotypes of the human body,including three germ layers.MsCs are multipotent progenitor cells possessing self-renewal ability(limited in vitro)and differentiation potential into mesenchymal lineages,according to the International Society for Cell and gene therapy(ISCT).This review provides an update on recent clinical applications using either hPSCs or MSCs derived from bone marrow(BM),adipose tissue(AT),or the umbilical cord(UC)for the treatment of human diseases,including neurological disorders,pulmonary dysfunctions,metabolic/endocrine-related diseases,reproductive disorders,skin burns,and cardiovascular conditions.Moreover,we discuss our own clinical trial experiences on targeted therapies using MsCs in a clinical setting,and we propose and discuss the MSC tissue origin concept and how MSC origin may contribute to the role of MSCs in downstream applications,with the ultimate objective of facilitating translational research in regenerative medicine into clinical applications.The mechanisms discussed here support the proposed hypothesis that BM-MSCs are potentially good candidates for brain and spinal cord injury treatment,AT-MSCs are potentially good candidates for reproductive disorder treatment and skin regeneration,and UC-MsCs are potentially good candidates for pulmonary disease and acute respiratory distress svndrometreatment.

关键词： diseases distress treatment

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Analysis of Significant genes and Pathways in Esophageal Cancer Based on gene Expression Omnibus Database

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Chinese Medical Sciences Journal 2023年第1期38卷 20-28页

作者： An-Yi Song Lan Mu Xiao-Yong Dai Li-Jun Wang Lai-Qiang Huang The Shenzhen Key Laboratory of gene and Antibody therapy State Key Laboratory of Chemical OncogenomicsTsinghua-Berkeley Shenzhen Institute(TBSI)Tsinghua Shenzhen International Graduate SchoolTsinghua UniversityShenzhen 518055Guangdong ProvinceChina Department of Chemistry Tsinghua UniversityBeijing 100084China

Objective To screen antigen targets for immunotherapy by analyzing over-expressed genes,and to identify significant pathways and molecular mechanisms in esophageal cancer by using bioinformatic methods such as enrichment analysis,protein-protein interaction(PPI)network,and survival analysis based on the gene Expression Omnibus(GEO)database.Methods By screening with highly expressed genes,we mainly analyzed proteins MUC13 and EPCAM with transmembrane domain and antigen epitope from TMHMM and IEDB websites.Significant genes and pathways associated with the pathogenesis of esophageal cancer were identified using enrichment analysis,PPI network,and survival analysis.Several software and platforms including Prism 8,R language,Cytoscape,DAVID,STRING,and GEPIA platform were used in the search and/or figure creation.Results genes MUC13 and EPCAM were over-expressed with several antigen epitopes in esophageal squamous cell carcinoma(ESCC)tissue.Enrichment analysis revealed that the process of keratinization was focused and a series of genes were related with the development of esophageal cancer.Four genes including ALDH3A1,C2,SLC6A1,and ZBTB7C were screened with significant P value of survival curve.Conclusions genes MUC13 and EPCAM may be promising antigen targets or biomarkers for esophageal cancer.Keratinization may greatly impact the pathogenesis of esophageal cancer.genes ALDH3A1,C2,SLC6A1,and ZBTB7C may play important roles in the development of esophageal cancer.

关键词： GEO esophageal cancer antigen enrichment analysis survival curve signaling pathway

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Spontaneous xenogeneic GvHD in Wilms'tumor Patient-Derived xenograft models and potential solutions

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Animal Models and Experimental Medicine 2022年第4期5卷 389-396页

作者： Seyed Mostafa Monzavi Ahad Muhammadnejad Maryam Behfar Amir Arsalan Khorsand Samad Muhammadnejad Abdol-Mohammad Kajbafzadeh Department of Applied Cell Sciences School of Advanced Technologies in MedicineTehran University of Medical SciencesTehranIran Pediatric Urology and Regenerative Medicine Research Center Tehran University of Medical SciencesTehranIran gene therapy Research Center Digestive Diseases Research InstituteTehran University of Medical SciencesTehranIran Cancer Biology Research Center Cancer Institute of IranTehran University of Medical SciencesTehranIran PDX Platform Biomarker Evaluation and Supervision Team for Personalized MedicineMolecular Tumor BoardCancer Institute of IranTehran University of Medical SciencesTehranIran Pediatric Cell and gene therapy Research Center Tehran University of Medical SciencesTehranIran

Severely immunocompromised NOD.Cg-PrkdcIl2rg(NOG)mice are among the ideal animal recipients for generation of human cancer models.Transplantation of human solid tumors having abundant tumor-i nfiltrating lymphocytes(TILs)can induce xenogeneic graft-versus-host disease(xGvHD)following engraftment and expansion of the TILs inside the animal body.Wilms’tumor(WT)has not been recognized as a lymphocyte-predominant tumor.However,3 consecutive generations of NOG mice bearing WT patient-derived xenografts(PDX)xenotransplanted from a single donor showed different degrees of inflammatory symptoms after transplantation before any therapeutic intervention.In the initial generation,dermatitis,auto-amputation of digits,weight loss,lymphadenopathy,hepatitis,and interstitial pneumonitis were observed.Despite antibiotic treatment,no response was noticed,and thus the animals were prematurely euthanized(day 47 posttransplantation).Laboratory and histopathologic evaluations revealed lymphoid infiltrates positively immunostained with anti-human CD3 and CD8 antibodies in the xenografts and primary tumor,whereas no microbial infection or lymphoproliferative disorder was found.Mice of the next generation that lived longer(91 days)developed sclerotic skin changes and more severe pneumonitis.Cutaneous symptoms were milder in the last generation.The xenografts of the last 2 generations also contained TILs,and lacked lymphoproliferative transformation.The systemic immunoinflammatory syndrome in the absence of microbial infection and posttransplant lymphoproliferative disorder was suggestive of xGvHD.While there are few reports of xGvHD in severely immunodeficient mice xenotransplanted from lymphodominant tumor xenografts,this report for the first time documented serial xGvHD in consecutive passages of WT PDX-bearing models and discussed potential solutions to prevent such an undesired complication.

关键词： graft-versus-host disease patient-derived xenograft models tumor-infiltrating lymphocytes Wilms’tumor

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