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Selection and characterization of the novel anti-human PD-1 FV78 antibody from a targeted epitope mammalian cell-displayed antibody library

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Cellular & Molecular immunology 2018年第2期15卷 146-157页

作者： Longlong Luo Shi Wang Xiaoling Lang Tingting Zhou Jing Geng Xinying Li Chunxia Qiao Jiannan Feng Beifen Shen Ming Lv Yan Li Laboratory of Immunology Institute of Basic Medical SciencesBeijing100850China laboratory of Cellular and Molecular immunology Institute of ImmunologyHenan UniversityKaifeng475001China

Currently,display-based methods are well established and widely used in antibody engineering for affinity maturation and structural stability improvement.We obtained a novel anti-human programmed death 1(PD-1)antibody using computer-aided design and a mammalian cell display technology platform.We used computer-aided modeling and distance geometry methods to predict and assign the key residues that contributed to the binding of human PD-L1 to PD-1.Then,we analyzed the sequence of nivolumab(an anti-human PD-1 antibody,referred to as MIL75 in the article)to determine the template for antibody design and library construction.We identified a series of potential substitutions on the obtained template and constructed a virtual epitope-targeted antibody library based on the physicochemical properties and each possible location of the assigned key residues.The virtual antibody libraries were displayed on the surface of mammalian cells as the antigen-binding fragments of full-length immunoglobulin G.Then,we used flow cytometry and sequencing approaches to sort and screen the candidates.Finally,we obtained a novel anti-human PD-1 antibody named FV78.FV78 competitively recognized the PD-1 epitopes that interacted with MIL75 and possessed an affinity comparable to MIL75.Our results implied that FV78 possessed equivalent bioactivity in vitro and in vivo compared with MIL75,which highlighted the probability and prospect of FV78 becoming a new potential antibody therapy.

关键词： antibody computer-guided modeling distance geometry human PD-1 mammalian cell-displayed antibody library

Natural evolution of hepatitis C virus infection in hemodialysis Tunisian patients and CTLA-4 SNP's

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World Journal of Gastroenterology 2015年第35期21卷 10150-10158页

作者： Leila Ksiaa Cheikhrouhou Yousr Lakhoua-Gorgi Imen Sfar Salwa Jendoubi-Ayed Houda Aouadi Mouna Makhlouf Khaled Ayed Taieb Ben Abdallah immunology Research laboratory of Kidney Transplantation and Immunopathology Laboratoire de Recherche Laboratory of Immunology Charles Nicolle Hospital

AIM: To analyze the polymorphisms of CTLA-4 gene involved in the response against hepatitis C virus(HCV) infection.METHODS: We recruited 500 hemodialysed patients from several hemodialysis centers, all HCV-antibody positive, spread over different regions of Tunisia, as part of a national survey in 2008 conducted in the Laboratory of Immunology at the Charles Nicolle hospital Tunisia, classified into two groups G1(PCR+) and G2(PCR-) according to the presence or absence of viral RNA. Of these patients, 307 were followed prospectively on a viral molecular level over a period from 2002 to 2008, divided into two groups based on the persistence and viral clearance. PCR-RFLP was performed for the analysis of SNPs(+49) A/G and(+6230) G/A CTLA-4 for these 500 patients and 358 healthy controls.RESULTS: Analysis of clinical and virological charac-teristics of our cohort suggests a nosocomial infection in our hemodialysed patients with transfusion history as a primary risk factor and a predominance of genotype 1b. The haplotype analysis revealed an increase of frequencies of GG(+49)/(CT60) CTLA-4 in the entire patients group compared to controls(P = 0.0036 and OR = 1.42; 95%CI: 1.12-1.79, respectively). This haplotype is therefore associated with susceptibility to HCV infection. CONCLUSION: Our study suggests a possible role of CTLA-4 polymorphisms in the outcome of HCV infection in the Tunisian hemodialysed population.

关键词： Hepatitis C virus Hemodialysis Natural evolution C

The chemokines CXCL8 and CXCL12:molecular and functional properties,role in disease and efforts towards pharmacological intervention

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Cellular & Molecular immunology 2023年第3期20卷 217-251页

作者： Seppe Cambier Mieke Gouwy Paul Proost laboratory of Molecular immunology Rega InstituteDepartment of MicrobiologyImmunology and TransplantationKU LeuvenLeuvenBelgium

Chemokines are an indispensable component of our immune system through the regulation of directional migration and activation of leukocytes.CxCL8 is the most potent human neutrophil-attracting chemokine and plays crucial roles in the response to infection and tissue injury.CXCL8 activity inherently depends on interaction with the human CXC chemokine receptors CXCR1 and CXCR2,the atypical chemokine receptor ACKR1,and glycosaminoglycans.Furthermore,(hetero)dimerization and tight regulation of transcription and translation,as well as post-translational modifications further fine-tune the spatial and temporal activity of CXCL8 in the context of inflammatory diseases and cancer.The CxCL8 interaction with receptors and glycosaminoglycans is therefore a promising target for therapy,as illustrated by multiple ongoing clinical trials.CXCL8-mediated neutrophil mobilization to blood is directly opposed by CXCL12,which retains leukocytes in bone marrow.CXCL12 is primarily a homeostatic chemokine that induces migration and activation of hematopoietic progenitor cells,endothelial cells,and several leukocytes through interaction with CXCR4,ACKR1,and ACKR3.Thereby,it is an essential player in the regulation of embryogenesis,hematopoiesis,and angiogenesis.However,CXCL12 can also exert inflammatory functions,as illustrated by its pivotal role in a growing list of pathologies and its synergy with CXCL8 and other chemokines to induce leukocyte chemotaxis.Here,we review the plethora of information on the CXCL8 structure,interaction with receptors and glycosaminoglycans,different levels of activity regulation,role in homeostasis and disease,and therapeutic prospects.Finally,we discuss recent research on CXCL12 biochemistry and biology and its role in pathology and pharmacology.

关键词： CXCL8 CXCL12 atypical chemokine receptor GPCR glycosaminoglycan

A small molecule cocktail breaks the bottleneck of human primary hepatocytes culture

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Science Bulletin 2019年第18期64卷 1293-1294页

作者： Yuchen Xia State Key laboratory of Virology and Hubei Province Key laboratory of Allergy and immunology and Department of immunology School of Basic Medical Sciences and Renmin Hospital of Wuhan University

It is estimated that more than 300 million people in China are suffering from different liver diseases including viral hepatitis,fatty liver,alcoholic liver,liver fibrosis,cirrhosis and liver cancer,of which about 400,000 people die each year[1].The clinical resolution of these diseases relies largely on the breakthroughs from basic research.Human primary hepatocytes(PHHs)have long been considered as the"gold standard"for in vitro liver disease research models.However,there are still a number of limitations,like high donor variability,short life spans and limited availability.

关键词： diseases clinical culture

HSP70L1-mediated intracellular priming of dendritic cell vaccination induces more potent CTL response against cancer

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Cellular & Molecular immunology 2018年第2期15卷 135-145页

作者： Shuxun Liu Lin Yi Ma Ling Jinxia Jiang Lijun Song Juan Liu Xuetao Cao National Key laboratory of Medical immunology Institute of ImmunologySecond Military Medical UniversityShanghai200433China Department of immunology National Key Laboratory of Medical Molecular BiologyChinese Academy of Medical SciencesBeijing100730China

Heat-shock protein(HSP)-based immunotherapy is established on its adjuvant effects when applied via an extracellular approach to pulse and activate dendritic cells(DCs).Our previous studies indicate that DCs pulsed with recombinant fusion proteins of antigenic fragment and HSP70-like protein 1(HSP70L1)are potent in stimulating antigen-specific Th1 responses.We herein evaluated the cytotoxic T cell(CTL)response by an intracellular approach of priming DCs with transfection of recombinant adenovirus-expressing the fusion gene of the 576–699 fragment of carcinoembryonic antigen(CEA)and HSP70L1.As compared with DCs pulsed with extracellular fusion protein,the DCs transfected with recombinant adenovirus expressing the fusion gene displayed equivalent mature phenotypes but less inflammatory appearance.However,the transfected DCs were superior to the pulsed DCs in inducing CEA-specific CTLs.Consistently,immunization of HLA-A2.1/H-2Kb transgene mice with the transfected DCs could induce more quantities of HLA-A2.1-restricted CEA-specific CTLs,protecting nude mice more significantly from human CEA-expressing colon tumor challenge when adoptively transferred.Mechanistic investigation indicated that intracellular expression of the fusion protein empowered the transfected DCs by activation of STAT1 possibly via inducing IFN-βand ERK pathways.Therefore,the more potent ability to induce anti-CEA CTL responses enables the DCs,which transfected with recombinant adenovirus expressing the fusion gene of antigenic CEA fragment and Th1 adjuvant,as an alternative promising approach for the immunotherapy of CEA-positive tumors.

关键词： CTL dendritic cell HSP70L1 immunotherapy

Inflammation-induced CD69^+ Kupffer cell feedback inhibits T cell proliferation via membrane-bound TGF-β1

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Science China(Life Sciences) 2016年第12期59卷 1259-1269页

作者： Xiang Zhang Zhengping Jiang Yan Gu Yanfang Liu Xuetao Cao Yanmei Han National Key laboratory of Medical immunology & Institute of immunology Second Military Medical University National Key laboratory of Medical Molecular Biology & Department of immunology Institute of Basic Medical SciencesChinese Academy of Medical Sciences

Kupffer cells,tissue-resident macrophage lineage cell,are enriched in vertebrate liver.The mouse F4/80^+ Kupffer cells have been subclassified into two subpopulations according to their phenotype and function:CD68^+ subpopulation with potent reactive oxygen species(ROS) production and phagocytic capacities,and CD11b^+ subpopulation with a potent capacity to produce T helper 1 cytokines.In addition,CD11b^+ Kupffer cells/macrophages may be migrated from the bone marrow or spleen,especially in inflammatory conditions of the liver.For analyzing diverse Kupffer cell subsets,we infected mice with Listeria monocytogenes and analyzed the phenotype variations of hepatic Kupffer cells.During L.monocytogenes infection,hepatic CD69^+ Kupffer cells were significantly induced and expanded,and CD69^+ Kupffer cells expressed higher level of CD11 b,and particularly high level of membrane-bound TGF-β1(mTGF-β1) but lower level of F4/80.We also found that clodronate liposome administration did not eliminate hepatic CD69^+ Kupffer cell subset.We consider the hepatic CD69^+ Kupffer cell population corresponds to CD11b^+Kupffer cells,the bone marrow-derived population.Hepatic CD69^+ Kupffer cells suppressed Ag-nonspecific and OVA-specific CD4 T cell proliferation through mTGF-β1 both in vitro and in vivo,meanwhile,they did not interfere with activation of CD4 T cells.Thus,we have identified a new subset of inflammation-induced CD69^+ Kupffer cells which can feedback inhibit CD4 T cell response via cell surface TGF-β1 at the late stage of immune response against infection.CD69^+ Kupffer cells may contribute to protect host from pathological injure by preventing overactivation of immune response.

关键词： Kupffer 房间有免疫力的规定 CD69 TGF-1 Listeria monocytogenes

Rescue of autoimmune hepatitis by soluble MHC class II molecules in an altered concanavalin A-induced experimental model

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Animal Models and Experimental Medicine 2020年第3期3卷 264-272页

作者： Katerina Bakela Maria Georgia Dimitraki Evangelia Skoufa Irene Athanassakis Laboratory of Immunology Department of BiologyUniversity of CreteHeraklionCreteGreece

Background:Soluble major histocompatibility complex class II(sMHCII)molecules have been described to maintain tolerance through the suppression of autoreactive T lymphocytes.In order to evaluate their ability to rescue autoimmune hepatitis(AIH)symptoms,the present work attempted to administer sMHCII molecules to an in vitro as well as in vivo concanavalin A(ConA)-induced AIH model.Methods:The in vitro AIH model consisted of splenocyte stimulation with ConA in the presence or absence of serum-isolated sMHCII molecules.An in vivo ConAmodified model with or without sMHCII treatment was developed.The cytokine profile in culture supernatants and serum was tested by ELISA.Cell markers were evaluated by immunofluorescence,while cell proliferation by tritiated thymidine uptake.AIH symptoms were assessed by daily observations for the establishment of a disease severity scoring system and liver histology was evaluated using a biomolecular imager.Results:The presence of sMHCII molecules in the ConA-stimulated cell cultures leads to a significant reduction of cell proliferation.The administration of sMHCII molecules to the ConA-treated animals showed a significant reduction in the levels of IL-2,IL-4,and IL-10,as well as a decrease in the number of spleen CD4+and CD8+cells.Upon development of a scoring system,it was shown that the sMHCII treatment was accompanied by a slower progression of the disease,while rescuing fibrotic liver morphology.Conclusion:The results presented in this study confirm the ability of sMHCII proteins to alleviate autoimmune hepatitis,possibly highlighting new therapeutic approaches for autoimmune diseases.

关键词： autoimmune hepatitis cytokines immunosuppression inflammation

The emerging role of Arid5a in cancer: A new target for tumors

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Genes & Diseases 2023年第3期10卷 813-824页

作者： Kishan Kumar Nyati Tadamitsu Kishimoto laboratory of Immune Regulation World Premier International Immunology Frontier Research CenterOsaka UniversityOsaka 5650871Japan

AT-rich interactive domain 5a (Arid5a) is a member of the arid family of proteins, which contain a helix-turn-helix domain and an ability to bind to nucleic acids. Current evidence suggests that Arid5a performs dual functions as a transcription factor and an RNA-binding protein in immune, nonimmune, and/ or tumor cells depending on its cellular localization. The contribution of Arid5a to the development of inflammation, autoimmunity, and obesity through its transcriptional and posttranscriptional regulatory functions has broadly been reviewed. Recent studies have indeed revealed an association of Arid5a with cancers, including breast, pancreatic, colorectal, and lung cancers and glioma. Notably, Arid5a affects various aspects of cellular homeostasis, including invasion, metastasis, epithelial-to-mesenchymal transition, immune evasion, adipogenesis and M1-like tumor-associated macrophage (TAM)-to-M2-like TAM transition. This review aims to summarize current knowledge of Arid5a from a cancer perspective and highlights recent advances in Arid5a-related cancer research. This review may improve the understanding of Arid5a-mediated molecular mechanisms and their relevance to cancers.

关键词： Arid5a Cancer Inflammation Metastasis Transcriptional and posttanscriptional regulation Tumor micr oenvir onment

Disparity of human immunodeficiency virus incidence and drug resistance in college student,non-student youth and older men who have sex with men:a cross-sectional study from seven major cities of China

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Chinese Medical Journal 2020年第23期133卷 2778-2786页

作者： Jing Zhang Jun-Jie Xu Zhen-Xing Chu Qing-Hai Hu Xiao-Xu Han Bin Zhao Yong-Jun Jiang Wen-Qing Geng Hong Shang NHC Key laboratory of AIDS immunology(China Medical University) National Clinical Research Center for Laboratory MedicineThe First Affiliated Hospital of China Medical UniversityShenyangLiaoning 110001China Key laboratory of AIDS immunology Chinese Academy of Medical SciencesShenyangLiaoning 110001China Key laboratory of AIDS immunology of Liaoning Province ShenyangLiaoning 110001China

Background:Human immunodeficiency virus(HIV)prevalence among student men who have sex with men(MSM)in college is more than 5.0%and keeps on increasing in China.This study aims to clarify the proportion of HIV recent infection,its propeller and the source among college student MSM.Methods:We conducted a multicenter cross-sectional study in seven major Chinese cities during 2012-2013.HIV recent infections(≤168 days)and incidence was measured and estimated by BED HIV-1 capture enzyme immunoassay(BED-CEIA)testing strategy.HIV-related behaviors and transmitted drug resistance(TDR)were investigated and compared between the college student MSM,<25-year-old non-student youth MSM(NSYM),and≥25-year-old non-student non-youth MSM(NSNYM),using structured survey,and analyses of drug resistance.Results:Overall,4496(4496/4526,99.3%)were eligible for enrollment,comprising 565 college student MSM,1094 NSYM,and 2837 NSNYM.The proportion of HIV recent infection were 70.3%(26/37),50.8%(65/128)and 35.1%(95/271),the HIV incidence rate were 10.0(95%CI:6.2-13.9)/100 person-year(PY),12.9(95%CI:9.8-16.1)/100PY,6.8(95%CI:5.4-8.2)/100 PY,and TDR prevalences were 7.4%(2/27),2.0%,(2/98)and 4.9%(11/226),among student MSM,NSYM,and NSNYM,respectively.Among HIV positive student MSM with age<21 years,the proportion of HIV recent infection is 90.9%(10/11).Factors independently associated with HIV recent infection in student MSM was usage of recreational drug in the past 6 months(adjusted odds ratio[aOR]:2.5;95%CI:1.0-5.8).Conclusions:College student MSM had higher proportion of HIV recent infection and TDR than the youth and older MSM in China during 2012-2013.The HIV infections were more likely to happen during the early year of college life among student MSM.

关键词： HIV incidence Drug resistance Men who have sex with men Male Students Cross-sectional studies Sexual behavior