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Wang Y, Song W, Xu Q, Liu Y, Liu H, Guo R, Chiou CJ, Gao K, Jin B, Chen C, Li Z, Yan J, Yu J. Adjuvant DNA vaccine pNMM promotes enhanced specific immunity and anti-tumor effects. Hum Vaccin Immunother 2023; 19:2202127. [PMID: 37128699 PMCID: PMC10142307 DOI: 10.1080/21645515.2023.2202127] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/03/2023] Open
Abstract
DNA vaccines containing only antigenic components have limited efficacy and may fail to induce effective immune responses. Consequently, adjuvant molecules are often added to enhance immunogenicity. In this study, we generated a tumor vaccine using a plasmid encoding NMM (NY-ESO-1/MAGE-A3/MUC1) target antigens and immune-associated molecules. The products of the vaccine were analyzed in 293 T cells by western blotting, flow cytometry, and meso-scale discovery electrochemiluminescence. To assess the immunogenicity obtained, C57BL/6 mice were immunized using the DNA vaccine. The results revealed that following immunization, this DNA vaccine induced cellular immune responses in C57BL/6 mice, as evaluated by the release of IFN-γ, and we also detected increases in the percentages of nonspecific lymphocytes, as well as those of antigen-specific T cells. Furthermore, immunization with the pNMM vaccine was found to significantly inhibit tumor growth and prolonged the survival of mice with B16-NMM+-tumors. Our data revealed that pNMM DNA vaccines not only confer enhanced immunity against tumors but also provide a potentially novel approach for vaccine design. Moreover, our findings provide a basis for further studies on vaccine pharmacodynamics and pharmacology, and lay a solid foundation for clinical application.
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Affiliation(s)
| | | | | | - Yachao Liu
- Gu'an Dingtai Haigui Biotechnology Co., Ltd., Peptide Valley Biomedical Incubation Port, Gu'an County, Hebei, China
| | - Hezhong Liu
- Gu'an Dingtai Haigui Biotechnology Co., Ltd., Peptide Valley Biomedical Incubation Port, Gu'an County, Hebei, China
| | - Runzi Guo
- Gu'an Dingtai Haigui Biotechnology Co., Ltd., Peptide Valley Biomedical Incubation Port, Gu'an County, Hebei, China
| | - Chuang-Jiun Chiou
- Gu'an Dingtai Haigui Biotechnology Co., Ltd., Peptide Valley Biomedical Incubation Port, Gu'an County, Hebei, China
| | - Kun Gao
- Gu'an Dingtai Haigui Biotechnology Co., Ltd., Peptide Valley Biomedical Incubation Port, Gu'an County, Hebei, China
| | - Baofeng Jin
- Gu'an Dingtai Haigui Biotechnology Co., Ltd., Peptide Valley Biomedical Incubation Port, Gu'an County, Hebei, China
| | - Changfeng Chen
- Gu'an Dingtai Haigui Biotechnology Co., Ltd., Peptide Valley Biomedical Incubation Port, Gu'an County, Hebei, China
| | - Zhongming Li
- Gu'an Dingtai Haigui Biotechnology Co., Ltd., Peptide Valley Biomedical Incubation Port, Gu'an County, Hebei, China
| | - Jinqi Yan
- Gu'an Dingtai Haigui Biotechnology Co., Ltd., Peptide Valley Biomedical Incubation Port, Gu'an County, Hebei, China
| | - Jiyun Yu
- Gu'an Dingtai Haigui Biotechnology Co., Ltd., Peptide Valley Biomedical Incubation Port, Gu'an County, Hebei, China
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Immunophenotypic Analysis of T Lymphocytes and Cytokine Production in Elderly Practicing Physical Activities and Its Relationship with Quality of Life and Depression. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:7985596. [PMID: 36193083 PMCID: PMC9526638 DOI: 10.1155/2022/7985596] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 09/12/2022] [Indexed: 11/18/2022]
Abstract
Aging is a complex process often associated with a chronic inflammatory profile that alters several biological functions, including the immune system and cognitive and physical capacity. The practice of physical activity is increasingly gaining popularity as a method of preventing infections, depression, and other disorders that affect the quality of life of the elderly. Thus, this work analyzes the profile of cytokines and molecular markers expressed in immune cells of elderly people who practice physical activities or not, evaluating their impacts on the immune system and quality of life. For this, 48 individuals were recruited, and peripheral blood samples were collected for hemogram analysis, cytokine determination, and immunophenotyping. Elderly people were separated into two groups: practitioners with low-intensity physical activity and non-practitioners. Quality of life was assessed using the Whoqol-Old instrument, and depression was assessed using the Beck II Depression Inventory. When comparing the scores of the Whoqol-Old and Beck questionnaires, we observed a significant negative correlation between these two factors. The perception of a higher quality of life was present in the elderly who exercised and was related to greater autonomy and sensory abilities, whereas the presence of depression was lower. In the hemogram, we observed higher basophil and segmented counts in the sedentary elderly, whereas lymphocytes and monocytes had lower counts. Elderly practitioners of physical activities had higher levels of IFN-γ, IL-4, and IL-10; increased expression of CD69, PD1, and TIM-3 in CD4+ T lymphocytes and increased CD14+CD80+ and CD14+CD86+ monocytes. Elderly people with an increased perception of quality of life had higher levels of IFN-γ, higher expression of CD14+CD80+CD86+, and decreased levels of TRAIL. An increase in TRAIL was observed in individuals with depression, in addition to an increased expression of CD14+CD86+. These results show a clear correlation between the quality of life, level of depression, physical activity, and immune system function. Although some cytokines with a typical proinflammatory profile (IFN-γ) were observed, the results point to a protective state with benefits reflected in the general well-being of the elderly who exercise.
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Zhang W, Le L, Ahmad G, Molehin AJ, Siddiqui AJ, Torben W, Karmakar S, Rojo JU, Sennoune S, Lazarus S, Khatoon S, Freeborn J, Sudduth J, Rezk AF, Carey D, Wolf RF, Papin JF, Damian R, Gray SA, Marks F, Carter D, Siddiqui AA. Fifteen Years of Sm-p80-Based Vaccine Trials in Nonhuman Primates: Antibodies From Vaccinated Baboons Confer Protection in vivo and in vitro From Schistosoma mansoni and Identification of Putative Correlative Markers of Protection. Front Immunol 2020; 11:1246. [PMID: 32636844 PMCID: PMC7318103 DOI: 10.3389/fimmu.2020.01246] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2020] [Accepted: 05/18/2020] [Indexed: 12/11/2022] Open
Abstract
Recent advances in systems biology have shifted vaccine development from a largely trial-and-error approach to an approach that promote rational design through the search for immune signatures and predictive correlates of protection. These advances will doubtlessly accelerate the development of a vaccine for schistosomiasis, a neglected tropical disease that currently affects over 250 million people. For over 15 years and with contributions of over 120 people, we have endeavored to test and optimize Sm-p80-based vaccines in the non-human primate model of schistosomiasis. Using RNA-sequencing on eight different Sm-p80-based vaccine strategies, we sought to elucidate immune signatures correlated with experimental protective efficacy. Furthermore, we aimed to explore the role of antibodies through in vivo passive transfer of IgG obtained from immunized baboons and in vitro killing of schistosomula using Sm-p80-specific antibodies. We report that passive transfer of IgG from Sm-p80-immunized baboons led to significant worm burden reduction, egg reduction in liver, and reduced egg hatching percentages from tissues in mice compared to controls. In addition, we observed that sera from Sm-p80-immunized baboons were able to kill a significant percent of schistosomula and that this effect was complement-dependent. While we did not find a universal signature of immunity, the large datasets generated by this study will serve as a substantial resource for further efforts to develop vaccine or therapeutics for schistosomiasis.
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Affiliation(s)
- Weidong Zhang
- Center for Tropical Medicine and Infectious Diseases, Texas Tech University Health Sciences Center, Lubbock, TX, United States
- Department of Internal Medicine, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, United States
| | - Loc Le
- Center for Tropical Medicine and Infectious Diseases, Texas Tech University Health Sciences Center, Lubbock, TX, United States
- Department of Internal Medicine, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, United States
| | - Gul Ahmad
- Department of Natural Sciences, Peru State College, Peru, NE, United States
| | - Adebayo J. Molehin
- Center for Tropical Medicine and Infectious Diseases, Texas Tech University Health Sciences Center, Lubbock, TX, United States
- Department of Internal Medicine, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, United States
| | | | - Workineh Torben
- Department of Biological Sciences, Louisiana State University of Alexandria, Alexandria, LA, United States
| | - Souvik Karmakar
- Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
| | - Juan U. Rojo
- Department of Molecular, Cellular and Biomedical Sciences, University of New Hampshire, Durham, NH, United States
| | - Souad Sennoune
- Center for Tropical Medicine and Infectious Diseases, Texas Tech University Health Sciences Center, Lubbock, TX, United States
- Department of Internal Medicine, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, United States
| | - Samara Lazarus
- Center for Tropical Medicine and Infectious Diseases, Texas Tech University Health Sciences Center, Lubbock, TX, United States
- Department of Internal Medicine, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, United States
| | - Sabiha Khatoon
- Center for Tropical Medicine and Infectious Diseases, Texas Tech University Health Sciences Center, Lubbock, TX, United States
- Department of Internal Medicine, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, United States
| | - Jasmin Freeborn
- Center for Tropical Medicine and Infectious Diseases, Texas Tech University Health Sciences Center, Lubbock, TX, United States
- Department of Internal Medicine, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, United States
| | - Justin Sudduth
- Center for Tropical Medicine and Infectious Diseases, Texas Tech University Health Sciences Center, Lubbock, TX, United States
- Department of Internal Medicine, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, United States
| | - Ashraf F. Rezk
- Center for Tropical Medicine and Infectious Diseases, Texas Tech University Health Sciences Center, Lubbock, TX, United States
- Department of Internal Medicine, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, United States
| | - David Carey
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
| | - Roman F. Wolf
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
- Oklahoma City VA Health Care System, Oklahoma City, OK, United States
| | - James F. Papin
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
| | - Ray Damian
- Department of Cellular Biology, University of Georgia, Athens, GA, United States
| | | | - Florian Marks
- International Vaccine Institute, SNU Research Park, Seoul, South Korea
- Department of Medicine, University of Cambridge, Cambridge, United Kingdom
| | - Darrick Carter
- PAI Life Sciences, Seattle, WA, United States
- Infectious Disease Research Institute, Seattle, WA, United States
| | - Afzal A. Siddiqui
- Center for Tropical Medicine and Infectious Diseases, Texas Tech University Health Sciences Center, Lubbock, TX, United States
- Department of Internal Medicine, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, United States
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McGowan E, Lin Q, Ma G, Yin H, Chen S, Lin Y. PD-1 disrupted CAR-T cells in the treatment of solid tumors: Promises and challenges. Biomed Pharmacother 2020; 121:109625. [PMID: 31733578 DOI: 10.1016/j.biopha.2019.109625] [Citation(s) in RCA: 108] [Impact Index Per Article: 21.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2019] [Revised: 10/27/2019] [Accepted: 10/31/2019] [Indexed: 12/13/2022] Open
Abstract
Unprecedented efficacy of chimeric antigen receptor (CAR) T cell therapy in the treatment of hematologic malignancies brings new hope for patients with many cancer types including solid tumors. However, the challenges for CAR-T cell therapy in eradicating solid tumors are immense. To overcome these seemingly intractable hurdles, more "powerful" CAR-T cells with enhanced antitumor efficacy are required. Emerging data support that the anti-tumor activity of CAR-T cells can be enhanced significantly without evident toxicity through simultaneous PD-1 disruption by genome editing. This review focuses on the current progress of PD-1 gene disrupted CAR-T cells in cancer therapy. Here we discuss key rationales for this new combination strategy and summarize the available pre-clinical studies. An update is provided on human clinical studies and available registered cancer clinical trials using CAR-T cells with PD-1 disruption. Future prospects and challenges are also discussed.
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Affiliation(s)
- Eileen McGowan
- Central Laboratory, First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China; School of Life Sciences, University of Technology Sydney, Sydney, Australia
| | - Qimou Lin
- Department of Surgery, Jiangmen Central Hospital, Jiangmen, Guangdong, China
| | - Guocai Ma
- Department of Anesthesiology, Jiangmen Central Hospital, Jiangmen, Guangdong, China
| | - Haibin Yin
- Guangzhou Anjie Biomedical Technology Co. Ltd, Guangzhou, China
| | - Size Chen
- Central Laboratory, First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China; Guangdong Provincial Engineering Research Center for Esophageal Cancer Precision Treatment, Guangzhou, China
| | - Yiguang Lin
- Central Laboratory, First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China; School of Life Sciences, University of Technology Sydney, Sydney, Australia.
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Marchiori C, Scarpa M, Kotsafti A, Morgan S, Fassan M, Guzzardo V, Porzionato A, Angriman I, Ruffolo C, Sut S, Dall’Acqua S, Bardini R, De Caro R, Castoro C, Scarpa M, Castagliuolo I. Epithelial CD80 promotes immune surveillance of colonic preneoplastic lesions and its expression is increased by oxidative stress through STAT3 in colon cancer cells. J Exp Clin Cancer Res 2019; 38:190. [PMID: 31072360 PMCID: PMC6509793 DOI: 10.1186/s13046-019-1205-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2018] [Accepted: 05/01/2019] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND One of the most potent costimulatory molecules involved in the recognition and killing of tumor cells is CD80. However, its role and the molecular mechanisms regulating its expression in sporadic colorectal carcinogenesis remain elusive. Here, we provide evidence for CD80 overexpression in human colon epithelial cells derived from preneoplastic mucosa. METHODS Expression of CD80 on colonic epithelial cells isolated from normal human colonic mucosa, preneoplastic and neoplastic specimens was assessed by flow cytometry. WT and CD80KO mice received azoxymethane to induce colon preneoplastic lesions and sacrificed to perform histology, flow cytometry analysis and immunohistochemistry of colonic mucosa. Some WT mice were treated with a monoclonal anti-CD80 antibody following AOM administration. Primary colon epithelial cells and CT26 cell line were used to quantify the expression of CD80 in response to pro-oxidant stimuli. Specific pharmacological inhibitors and siRNA silencing were used to inhibit MAPK pathways and STAT3. RESULTS CD80 expression was significantly increased in colon epithelial cells of human preneoplastic lesions. In the AOM model, CD80 impairment by administration of neutralizing antibodies or use of CD80 knockout mice enhanced dysplasia development. In vitro, CD80 upregulation was induced by oxidative stress in colon cancer cells and primary colon epithelial cells. In addition, reactive oxygen species could induce CD80 expression via the JNK and p38 MAPK pathways, that activated STAT3 transcription factor in colon cancer epithelial cells. CONCLUSION This study provide evidence for a major role of CD80 in orchestrating immune surveillance of colon preneoplastic lesions and might help to develop novel approaches that exploit anti-tumor immunity to prevent and control colon cancer.
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Affiliation(s)
- Chiara Marchiori
- Department of Molecular Medicine DMM, University of Padua, Padua, Italy
| | - Melania Scarpa
- Laboratory of Advanced Translational Research, Veneto Institute of Oncology IOV – IRCCS, via Gattamelata 64, 35128 Padua, Italy
| | - Andromachi Kotsafti
- Laboratory of Advanced Translational Research, Veneto Institute of Oncology IOV – IRCCS, via Gattamelata 64, 35128 Padua, Italy
| | - Susan Morgan
- Pathology Unit, Sheffield Teaching Hospitals, Sheffield, UK
| | - Matteo Fassan
- Surgical Pathology Unit from the Department of Medicine DIMED, University of Padua, Padua, Italy
| | - Vincenza Guzzardo
- Surgical Pathology Unit from the Department of Medicine DIMED, University of Padua, Padua, Italy
| | | | - Imerio Angriman
- General Surgery Unit from the Department of Surgery, Oncology and Gastroenterology DISCOG, University of Padua, Padua, Italy
| | - Cesare Ruffolo
- General Surgery Unit (IV), Ca’ Foncello Hospital, Treviso, Italy
| | - Stefania Sut
- Department of Pharmaceutical and Pharmacological Sciences DSF, University of Padua, Padua, Italy
| | - Stefano Dall’Acqua
- Department of Pharmaceutical and Pharmacological Sciences DSF, University of Padua, Padua, Italy
| | - Romeo Bardini
- General Surgery Unit from the Department of Surgery, Oncology and Gastroenterology DISCOG, University of Padua, Padua, Italy
| | | | - Carlo Castoro
- Laboratory of Advanced Translational Research, Veneto Institute of Oncology IOV – IRCCS, via Gattamelata 64, 35128 Padua, Italy
| | - Marco Scarpa
- Laboratory of Advanced Translational Research, Veneto Institute of Oncology IOV – IRCCS, via Gattamelata 64, 35128 Padua, Italy
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Badmazhapova DS, Gal’tseva IV, Zvonkov EE. Immunological Synapse in the Biology of Chronic Lymphocytic Leukemia. ACTA ACUST UNITED AC 2018. [DOI: 10.21320/2500-2139-2018-11-4-313-318] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Current status and perspectives of chimeric antigen receptor modified T cells for cancer treatment. Protein Cell 2017; 8:896-925. [PMID: 28466386 PMCID: PMC5712290 DOI: 10.1007/s13238-017-0400-z] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2016] [Accepted: 03/15/2017] [Indexed: 12/21/2022] Open
Abstract
Chimeric antigen receptor (CAR) is a recombinant immunoreceptor combining an antibody-derived targeting fragment with signaling domains capable of activating cells, which endows T cells with the ability to recognize tumor-associated surface antigens independent of the expression of major histocompatibility complex (MHC) molecules. Recent early-phase clinical trials of CAR-modified T (CAR-T) cells for relapsed or refractory B cell malignancies have demonstrated promising results (that is, anti-CD19 CAR-T in B cell acute lymphoblastic leukemia (B-ALL)). Given this success, broadening the clinical experience of CAR-T cell therapy beyond hematological malignancies has been actively investigated. Here we discuss the basic design of CAR and review the clinical results from the studies of CAR-T cells in B cell leukemia and lymphoma, and several solid tumors. We additionally discuss the major challenges in the further development and strategies for increasing anti-tumor activity and safety, as well as for successful commercial translation.
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Herr F, Brunel M, Roders N, Durrbach A. Co-stimulation Blockade Plus T-Cell Depletion in Transplant Patients: Towards a Steroid- and Calcineurin Inhibitor-Free Future? Drugs 2016; 76:1589-1600. [DOI: 10.1007/s40265-016-0656-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Gil-Jaramillo N, Motta FN, Favali CBF, Bastos IMD, Santana JM. Dendritic Cells: A Double-Edged Sword in Immune Responses during Chagas Disease. Front Microbiol 2016; 7:1076. [PMID: 27471496 PMCID: PMC4943928 DOI: 10.3389/fmicb.2016.01076] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2016] [Accepted: 06/27/2016] [Indexed: 01/24/2023] Open
Abstract
Dendritic cells (DCs) are the most important member of the antigen presenting cells group due to their ability to recognize antigen at the infection site and their high specialized antigen internalization capacity. These cells have central role in connecting the innate and adaptive immune responses against Trypanosoma cruzi, the causative agent of Chagas disease. These first line defense cells modulate host immune response depending on type, maturation level, cytokine milieu and DC receptor involved in the interactions with T. cruzi, influencing the development of the disease clinic forms. Here, we present a review of DCs-T. cruzi interactions both in human and murine models, pointing out the parasite ability to manipulate DCs activity for the purpose of evading innate immune response and assuring its own survival and persistence.
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Affiliation(s)
- Natalia Gil-Jaramillo
- Laboratório de Interação Patógeno-Hospedeiro, Instituto de Biologia, Universidade de BrasíliaBrasília, Brazil
| | - Flávia N. Motta
- Laboratório de Interação Patógeno-Hospedeiro, Instituto de Biologia, Universidade de BrasíliaBrasília, Brazil
- Faculdade de Ceilândia, Universidade de BrasíliaBrasília, Brazil
| | - Cecília B. F. Favali
- Laboratório de Biologia do Gene, Instituto de Biologia, Universidade de BrasíliaBrasília, Brazil
| | - Izabela M. D. Bastos
- Laboratório de Interação Patógeno-Hospedeiro, Instituto de Biologia, Universidade de BrasíliaBrasília, Brazil
| | - Jaime M. Santana
- Laboratório de Interação Patógeno-Hospedeiro, Instituto de Biologia, Universidade de BrasíliaBrasília, Brazil
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Kubota A, Hasegawa H, Tadokoro H, Hirose M, Kobara Y, Yamada-Inagawa T, Takemura G, Kobayashi Y, Takano H. Deletion of CD28 Co-stimulatory Signals Exacerbates Left Ventricular Remodeling and Increases Cardiac Rupture After Myocardial Infarction. Circ J 2016; 80:1971-9. [PMID: 27396441 DOI: 10.1253/circj.cj-16-0327] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
BACKGROUND Inflammatory responses, especially by CD4(+)T cells activated by dendritic cells, are known to be important in the pathophysiology of cardiac repair after myocardial infarction (MI). Although co-stimulatory signals through B7 (CD80/86) and CD28 are necessary for CD4(+)T cell activation and survival, the roles of these signals in cardiac repair after MI are still unclear. METHODS AND RESULTS C57BL/6 (Control) mice and CD28 knockout (CD28KO) mice were subjected to left coronary artery permanent ligation. The ratio of death by cardiac rupture within 5 days after MI was significantly higher in CD28KO mice compared with Control mice. Although there were no significant differences in the infarct size between the 2 groups, left ventricular end-diastolic and end-systolic diameters were significantly increased, and fractional shortening was significantly decreased in CD28KO mice compared with Control mice. Electron microscopic observation revealed that the extent of extracellular collagen fiber was significantly decreased in CD28KO mice compared with Control mice. The number of α-smooth muscle actin-positive myofibroblasts was significantly decreased, and matrix metalloproteinase-9 activity and the mRNA expression of interleukin-1β were significantly increased in CD28KO mice compared with Control mice. CONCLUSIONS Deletion of CD28 co-stimulatory signals exacerbates left ventricular remodeling and increases cardiac rupture after MI through prolongation of the inflammatory period and reduction of collagen fiber in the infarct scars. (Circ J 2016; 80: 1971-1979).
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Affiliation(s)
- Akihiko Kubota
- Department of Cardiovascular Medicine, Chiba University Graduate School of Medicine
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Emerging therapies provide new opportunities to reshape the multifaceted interactions between the immune system and lymphoma cells. Leukemia 2016; 30:1805-15. [PMID: 27389058 DOI: 10.1038/leu.2016.161] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2016] [Revised: 05/04/2016] [Accepted: 05/10/2016] [Indexed: 12/21/2022]
Abstract
The acquisition of a complete neoplastic phenotype requires cancer cells to develop escape mechanisms from the host immune system. This phenomenon, commonly referred to as 'immune evasion,' represents a hallmark of cancers and results from a Darwinian selection of the fittest tumor clones. First reported in solid tumors, cancer immunoescape characterizes several hematological malignancies. The biological bases of cancer immunoescape have recently been disclosed and include: (i) impaired human leukocyte antigen-mediated cancer cell recognition (B2M, CD58, CTIIA, CD80/CD86, CD28 and CTLA-4 mutations); (ii) deranged apoptotic mechanisms (reduced pro-apoptotic signals and/or increased expression of anti-apoptotic molecules); and (iii) changes in the tumor microenvironment involving regulatory T cells and tumor-associated macrophages. These immune-escape mechanisms characterize both Hodgkin and non-Hodgkin (B and T cell) lymphomas and represent a promising target for new anti-tumor therapies. In the present review, the principles of cancer immunoescape and their role in human lymphomagenesis are illustrated. Current therapies targeting these pathways and possible applications for lymphoma treatment are also addressed.
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Yin X, Wang W, Zhu X, Wang Y, Wu S, Wang Z, Wang L, Du Z, Gao J, Yu J. Synergistic antitumor efficacy of combined DNA vaccines targeting tumor cells and angiogenesis. Biochem Biophys Res Commun 2015; 465:239-44. [PMID: 26253468 DOI: 10.1016/j.bbrc.2015.08.003] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Accepted: 08/01/2015] [Indexed: 01/12/2023]
Abstract
To further enhance the antitumor efficacy of DNA vaccine, we proposed a synergistic strategy that targeted tumor cells and angiogenesis simultaneously. In this study, a Semliki Forest Virus (SFV) replicon DNA vaccine expressing 1-4 domains of murine VEGFR2 and IL12 was constructed, and was named pSVK-VEGFR2-GFc-IL12 (CAVE). The expression of VEGFR2 antigen and IL12 adjuvant molecule in 293T cells in vitro were verified by western blot and enzyme-linked immune sorbent assay (ELISA). Then CAVE was co-immunized with CAVA, a SFV replicon DNA vaccine targeting survivin and β-hCG antigens constructed previously. The antitumor efficacy of our combined replicon vaccines was evaluated in mice model and the possible mechanism was further investigated. The combined vaccines could elicit efficient humoral and cellular immune responses against survivin, β-hCG and VEGFR2 simultaneously. Compared with CAVE or CAVA vaccine alone, the combined vaccines inhibited the tumor growth and improved the survival rate in B16 melanoma mice model more effectively. Furthermore, the intratumoral microvessel density was lowest in combined vaccines group than CAVE or CAVA alone group. Therefore, this synergistic strategy of DNA vaccines for tumor treatment results in an increased antitumor efficacy, and may be more suitable for translation to future research and clinic.
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Affiliation(s)
- Xiaotao Yin
- Department of Urology, Chinese PLA General Hospital, 28 Fu Xing Road, Beijing 100853, China; Beijing Institute of Basic Medical Sciences, 27 Tai Ping Road, Beijing 100850, China
| | - Wei Wang
- Beijing Institute of Basic Medical Sciences, 27 Tai Ping Road, Beijing 100850, China; Department of Urology, No. 261 Hospital of PLA, Beijing, China
| | - Xiaoming Zhu
- Beijing Institute of Basic Medical Sciences, 27 Tai Ping Road, Beijing 100850, China
| | - Yu Wang
- Beijing Institute of Basic Medical Sciences, 27 Tai Ping Road, Beijing 100850, China
| | - Shuai Wu
- Beijing Institute of Basic Medical Sciences, 27 Tai Ping Road, Beijing 100850, China
| | - Zicheng Wang
- Beijing Institute of Basic Medical Sciences, 27 Tai Ping Road, Beijing 100850, China
| | - Lin Wang
- Department of Internal Medicine, No. 316 Hospital of PLA, Beijing, China
| | - Zhiyan Du
- Beijing Institute of Basic Medical Sciences, 27 Tai Ping Road, Beijing 100850, China
| | - Jiangping Gao
- Department of Urology, Chinese PLA General Hospital, 28 Fu Xing Road, Beijing 100853, China.
| | - Jiyun Yu
- Beijing Institute of Basic Medical Sciences, 27 Tai Ping Road, Beijing 100850, China.
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Shankar EM, Velu V, Kamarulzaman A, Larsson M. Mechanistic insights on immunosenescence and chronic immune activation in HIV-tuberculosis co-infection. World J Virol 2015; 4:17-24. [PMID: 25674514 PMCID: PMC4308524 DOI: 10.5501/wjv.v4.i1.17] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2014] [Revised: 09/30/2014] [Accepted: 10/27/2014] [Indexed: 02/06/2023] Open
Abstract
Immunosenescence is marked by accelerated degradation of host immune responses leading to the onset of opportunistic infections, where senescent T cells show remarkably higher ontogenic defects as compared to healthy T cells. The mechanistic association between T-cell immunosenescence and human immunodeficiency virus (HIV) disease progression, and functional T-cell responses in HIV-tuberculosis (HIV-TB) co-infection remains to be elaborately discussed. Here, we discussed the association of immunosenescence and chronic immune activation in HIV-TB co-infection and reviewed the role played by mediators of immune deterioration in HIV-TB co-infection necessitating the importance of designing therapeutic strategies against HIV disease progression and pathogenesis.
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Limited density of an antigen presented by RMA-S cells requires B7-1/CD28 signaling to enhance T-cell immunity at the effector phase. PLoS One 2014; 9:e108192. [PMID: 25383875 PMCID: PMC4226464 DOI: 10.1371/journal.pone.0108192] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2014] [Accepted: 08/25/2014] [Indexed: 11/19/2022] Open
Abstract
The association of B7-1/CD28 between antigen presenting cells (APCs) and T-cells provides a second signal to proliferate and activate T-cell immunity at the induction phase. Many reports indicate that tumor cells transfected with B7-1 induced augmented antitumor immunity at the induction phase by mimicking APC function; however, the function of B7-1 on antitumor immunity at the effector phase is unknown. Here, we report direct evidence of enhanced T-cell antitumor immunity at the effector phase by the B7-1 molecule. Our experiments in vivo and in vitro indicated that reactivity of antigen-specific monoclonal and polyclonal T-cell effectors against a Lass5 epitope presented by RMA-S cells is increased when the cells expressed B7-1. Use of either anti-B7-1 or anti-CD28 antibodies to block the B7-1/CD28 association reduced reactivity of the T effectors against B7-1 positive RMA-S cells. Transfection of Lass5 cDNA into or pulse of Lass5 peptide onto B7-1 positive RMA-S cells overcomes the requirement of the B7-1/CD28 signal for T effector response. To our knowledge, the data offers, for the first time, strong evidence that supports the requirement of B7-1/CD28 secondary signal at the effector phase of antitumor T-cell immunity being dependent on the density of an antigenic peptide.
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15
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Zhang L, Wang Y, Xiao Y, Wang Y, Dong J, Gao K, Gao Y, Wang X, Zhang W, Xu Y, Yan J, Yu J. Enhancement of antitumor immunity using a DNA-based replicon vaccine derived from Semliki Forest virus. PLoS One 2014; 9:e90551. [PMID: 24608380 PMCID: PMC3946523 DOI: 10.1371/journal.pone.0090551] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2013] [Accepted: 02/02/2014] [Indexed: 01/28/2023] Open
Abstract
A DNA-based replicon vaccine derived from Semliki Forest virus, PSVK-shFcG-GM/B7.1 (Fig. 1a) was designed for tumor immunotherapy as previously constructed. The expression of the fusion tumor antigen (survivin and hCGβ-CTP37) and adjuvant molecular protein (Granulocyte-Macrophage Colony-Stimulating Factor/ GM-CSF/B7.1) genes was confirmed by Immunofluorescence assay in vitro, and immunohistochemistry assay in vivo. In this paper, the immunological effect of this vaccine was determined using immunological assays as well as animal models. The results showed that this DNA vaccine induced both humoral and cellular immune responses in C57BL/6 mice after immunization, as evaluated by the ratio of CD4+/CD8+ cells and the release of IFN-γ. Furthermore, the vaccination of C57BL/6 mice with PSVK-shFcG-GM/B7.1 significantly delayed the in vivo growth of tumors in animal models (survivin+ and hCGβ+ murine melanoma, B16) when compared to vaccination with the empty vector or the other control constructs (Fig. 1b). These data indicate that this type of replicative DNA vaccine could be developed as a promising approach for tumor immunotherapy. Meanwhile, these results provide a basis for further study in vaccine pharmacodynamics and pharmacology, and lay a solid foundation for clinical application.
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Affiliation(s)
- Liang Zhang
- Beijing Institute of Basic Medical Sciences, Haidian district, Beijing, China
| | - Yue Wang
- Beijing Institute of Basic Medical Sciences, Haidian district, Beijing, China
- National Center for AIDS/STD Control and Prevention, China-CDC, Beijing, China
| | - Yi Xiao
- Beijing Institute of Basic Medical Sciences, Haidian district, Beijing, China
- Department of Urology, First Affiliated Hospital of General Hospital of PLA, Beijing, China
| | - Yu Wang
- Beijing Institute of Basic Medical Sciences, Haidian district, Beijing, China
| | - JinKai Dong
- Beijing Institute of Basic Medical Sciences, Haidian district, Beijing, China
| | - Kun Gao
- Beijing Institute of Basic Medical Sciences, Haidian district, Beijing, China
| | - Yan Gao
- Beijing Institute of Basic Medical Sciences, Haidian district, Beijing, China
| | - Xi Wang
- Beijing Institute of Basic Medical Sciences, Haidian district, Beijing, China
| | - Wei Zhang
- Beijing Institute of Basic Medical Sciences, Haidian district, Beijing, China
| | - YuanJi Xu
- Beijing Institute of Basic Medical Sciences, Haidian district, Beijing, China
| | - JinQi Yan
- Beijing Institute of Basic Medical Sciences, Haidian district, Beijing, China
| | - JiYun Yu
- Beijing Institute of Basic Medical Sciences, Haidian district, Beijing, China
- * E-mail:
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16
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Abstract
T cell activation is a key event in the adaptive immune response and vital to the generation of both cellular and humoral immunity. Activation is required not only for effective CD4 T cell responses but also to provide help for B cells and the generation of cytotoxic T cell responses. Unsurprisingly, impaired T cell activation results in infectious pathology, whereas dysregulated activation can result in autoimmunity. The decision to activate is therefore tightly regulated and the CD28/CTLA-4 pathway represents this apical decision point at the molecular level. In particular, CTLA-4 (CD152) is an essential checkpoint control for autoimmunity; however, the molecular mechanism(s) by which CTLA-4 achieves its regulatory function are not well understood, especially how it functionally intersects with the CD28 pathway. In this chapter, we review the established molecular and cellular concepts relating to CD28 and CTLA-4 biology, and attempt to integrate these by discussing the transendocytosis of ligands as a new model of CTLA-4 function.
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Affiliation(s)
- Blagoje Soskic
- School of Immunity and Infection, University of Birmingham, Birmingham, United Kingdom
| | | | - Tiezheng Hou
- UCL Institute of Immunity and Transplantation, Royal Free Campus, London, United Kingdom
| | - David M Sansom
- UCL Institute of Immunity and Transplantation, Royal Free Campus, London, United Kingdom.
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Comparative antitumor effect of preventive versus therapeutic vaccines employing B16 melanoma cells genetically modified to express GM-CSF and B7.2 in a murine model. Toxins (Basel) 2012. [PMID: 23202306 PMCID: PMC3509698 DOI: 10.3390/toxins4111058] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Cancer vaccines have always been a subject of gene therapy research. One of the most successful approaches has been working with genetically modified tumor cells. In this study, we describe our approach to achieving an immune response against a murine melanoma model, employing B16 tumor cells expressing GM-CSF and B7.2. Wild B16 cells were injected in C57BL6 mice to cause the tumor. Irradiated B16 cells transfected with GM-CSF, B7.2, or both, were processed as a preventive and therapeutic vaccination. Tumor volumes were measured and survival curves were obtained. Blood samples were taken from mice, and IgGs of each treatment group were also measured. The regulatory T cells (Treg) of selected groups were quantified using counts of images taken by confocal microscopy. Results: one hundred percent survival was achieved by preventive vaccination with the group of cells transfected with p2F_GM-CSF. Therapeutic vaccination achieved initial inhibition of tumor growth but did not secure overall survival of the animals. Classical Treg cells did not vary among the different groups in this therapeutic vaccination model.
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18
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Baccatin III, a synthetic precursor of taxol, enhances MHC-restricted antigen presentation in dendritic cells. Int Immunopharmacol 2011; 11:985-91. [DOI: 10.1016/j.intimp.2011.02.013] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2010] [Revised: 02/08/2011] [Accepted: 02/09/2011] [Indexed: 11/21/2022]
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19
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Jin LP, Fan DX, Zhang T, Guo PF, Li DJ. The costimulatory signal upregulation is associated with Th1 bias at the maternal-fetal interface in human miscarriage. Am J Reprod Immunol 2011; 66:270-8. [PMID: 21481059 DOI: 10.1111/j.1600-0897.2011.00997.x] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
PROBLEM To evaluate whether the association of the costimulatory signal regulation with T helper 1/T helper 2 (Th1/Th2) bias at maternal-fetal interface in human pregnancy loss. METHOD OF STUDY The expression of CD80 and CD86 in decidual tissues and CD28 and cytotoxic T-lymphocyte antigen-4 (CTLA-4) in the decidual T cells was compared between normal early pregnancy and miscarriage by qPCR and Western blot. The cytokine production in decidual T cells was performed by flow cytometry. The correlation of costimulatory molecule expression with Th1/Th2 cytokines was analyzed. RESULTS The CD80 mRNA and protein expression showed no significant difference between normal pregnancy and miscarriage. An increase in the expression of CD28 and CD86 was accompanied by a decrease in the expression of CTLA-4 in miscarriage in comparison with the early pregnancy. The higher expression of interleukin (IL)-2 and interferon-γ (IFN-γ), and lower expression of IL-4 and IL-10 in the decidual T cells were present in miscarriage. A correlation analysis showed a significant positive correlation of CD86 and CD28 expression with the Th1 cytokine production (IL-2 and IFN-γ), a significant negative correlation of CTLA-4 expression with the Th1 cytokine production. CONCLUSION The upregualtion of costimulatory signals on T cells might form an abnormal immune microenvironment, a shift to Th1 responses, at maternal-fetal interface, which leads to human miscarriage.
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Affiliation(s)
- Li-Ping Jin
- Laboratory for Reproductive Immunology, Hospital and Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College, China
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20
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Jin LP, Fan DX, Li DJ. Regulation of costimulatory signal in maternal-fetal immune tolerance. Am J Reprod Immunol 2011; 66:76-83. [PMID: 21276120 DOI: 10.1111/j.1600-0897.2010.00982.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
A pregnancy is associated with modifications in the immune status of the mother, but the mechanisms are not well understood. Several observations have indicated that CD28/CTLA-4 and B7-1/B7-2 are involved in the maternal-fetal immune regulation. This review aims to recapitulate our current knowledge concerning the role of CD28/CTLA-4 and B7-1/B7-2 in maternal-fetal immune regulation. Several studies suggest that up-regulation of B7-2 and/or CD28 and/or down-regulation of CTLA-4 are correlated with the occurrence of pregnancy loss. Therefore, an accurate expression of costimulatory molecules at the maternal-fetal interface may ensure that the decidual cells do not elicit a 'danger' signal to the maternal immune system, perhaps instead contributing to the establishment of immune tolerance in vivo. It is showed that costimulation blockade with anti-B7 mAbs results in altered allogeneic T-cell response and overcomes increased maternal rejection to the fetus, which improves fetus growth in the abortion-prone system. These findings suggest that the anti-B7-treated T cells not only function as potent suppresser cells but also exert immunoregulatory effect on the maternal T cells. This procedure might be potentially useful to immunotherapy for human recurrent spontaneous abortion.
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Affiliation(s)
- Li-Ping Jin
- Laboratory for Reproductive Immunology, Hospital and Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai, China
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21
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Dai ZS, Chen QF, Lu HZ, Xie Y. Defective expression and modulation of B7-2/CD86 on B cells in B cell chronic lymphocytic leukemia. Int J Hematol 2009; 89:656-63. [PMID: 19430862 DOI: 10.1007/s12185-009-0320-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2008] [Revised: 03/26/2009] [Accepted: 04/07/2009] [Indexed: 12/01/2022]
Abstract
Malignant monoclonal B cells of chronic B cell lymphocytic leukemia (B-CLL) usually fail to be cleared, which indicates important costimulatory molecules may be lacking. Among those costimulatory signals, B7-1/CD80 and B7-2/CD86 caused utmost attention. In this study, B7-1 and B7-2 expression on B cells in chronic B cell lymphocytic leukemia patients were detected. Data showed that B7-2 expression in chronic B cell lymphocytic leukemia patients is significantly lower than in normal people, which suggests defective B7-2 expression may be one of the pathogenic mechanisms of chronic B cell lymphocytic leukemia. Further, we confirmed interferon-gamma could induce B7-2 expression slightly and promote T-cell response against chronic B cell lymphocytic leukemia cells, indicating interferon-gamma has clinical value in chronic leukemia immunotherapy based on modulating B7-2 expression.
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Affiliation(s)
- Zhen-sheng Dai
- Department of Infectious Disease, Shanghai Public Health Clinical Center affiliated to Fudan University, Jinshan District, Shanghai, People's Republic of China.
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22
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Quinn K, Henriques M, Parker T, Slutsky AS, Zhang H. Human neutrophil peptides: a novel potential mediator of inflammatory cardiovascular diseases. Am J Physiol Heart Circ Physiol 2008; 295:H1817-24. [PMID: 18805897 PMCID: PMC4896811 DOI: 10.1152/ajpheart.00472.2008] [Citation(s) in RCA: 66] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The traditional view of atherosclerosis has recently been expanded from a predominantly lipid retentive disease to a coupling of inflammatory mechanisms and dyslipidemia. Studies have suggested a novel role for polymorphonuclear neutrophil (PMN)-dominant inflammation in the development of atherosclerosis. Human neutrophil peptides (HNPs), also known as alpha-defensins, are secreted and released from PMN granules upon activation and are conventionally involved in microbial killing. Current evidence suggests an important immunomodulative role for these peptides. HNP levels are markedly increased in inflammatory diseases including sepsis and acute coronary syndromes. They have been found within the intima of human atherosclerotic arteries, and their deposition in the skin correlates with the severity of coronary artery diseases. HNPs form complexes with LDL in solution and increase LDL binding to the endothelial surface. HNPs have also been shown to contribute to endothelial dysfunction, lipid metabolism disorder, and the inhibition of fibrinolysis. Given the emerging relationship between PMN-dominant inflammation and atherosclerosis, HNPs may serve as a link between them and as a biological marker and potential therapeutic target in cardiovascular diseases including coronary artery diseases and acute coronary syndromes.
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Affiliation(s)
- Kieran Quinn
- The Keenan Research Centre in the Li Ka Shing Knowledge Institute of Saint Michael's Hospital, Toronto, ON, Canada
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23
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T lymphocytes in Sjögren's syndrome: contributors to and regulators of pathophysiology. Clin Rev Allergy Immunol 2008; 32:252-64. [PMID: 17992592 DOI: 10.1007/s12016-007-8011-8] [Citation(s) in RCA: 80] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Sjögren's syndrome is a chronic autoimmune disorder characterized by lymphocytic infiltration and malfunction of the exocrine glands, resulting in dry mouth and eyes. This multigenic and multifunctional disease can present as primary Sjögren's syndrome or secondary to an underlying connective tissue disease. Immune activation subsequent to activation or apoptosis of glandular epithelial cells in genetically predisposed individuals may expose autoantigens, which engage self-perpetuating T cell dependent autoimmune sequelae. The cellular and molecular context of this immune response may drive proinflammatory (Th1 and Th17) and restrain inhibitory (Treg) pathways. Inability to suppress the immune response results in persistent tissue damage and compromised function of salivary and lacrimal glands. Defining the contributions of participating T cells may unravel strategies for therapeutic intervention.
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24
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Abstract
"T-bodies" are genetically engineered T cells armed with chimeric receptors whose extracellular recognition unit is comprised of an antibody-derived recognition domain and whose intracellular region is derived from lymphocyte stimulating moiety(ies). The structure of the prototypic chimeric receptor, also known as a chimeric immune receptor, is modular, designed to accomodate various functional domains and thereby to enable choice of specificity and controlled activation of T cells. The preferred antibody-derived recognition unit is a single chain variable fragment (scFv) that combines the specificity and binding residues of both the heavy and light chain variable regions of a monoclonal antibody. The most common lymphocyte activation moieties include a T-cell costimulatory (e.g. CD28) domain in tandem with a T-cell triggering (e.g. CD3zeta) moiety. By arming effector lymphocytes (such as T cells and natural killer cells) with such chimeric receptors, the engineered cell is redirected with a predefined specificity to any desired target antigen, in a non-HLA restricted manner. Chimeric receptor (CR) constructs are introduced ex vivo into T cells from peripheral lymphocytes of a given patient using retroviral vectors. Following infusion of the resulting T-bodies back into the patient, they traffic, reach their target site, and upon interaction with their target cell or tissue, they undergo activation and perform their predefined effector function. Therapeutic targets for the T-body approach include cancer and HIV-infected cells, or autoimmune effector cells. To date, the most investigated area is cancer therapy. Here, the T-bodies are advantageous because their tumor recognition is not HLA-specific and, therefore, the same constructs can be used for a wide spectrum of patients and cancers.
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Affiliation(s)
- Z Eshhar
- Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel.
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25
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Lee YH, Lee YR, Im SA, Park SI, Kim KH, Gerelchuluun T, Song S, Kim K, Lee CK. Calcineurin inhibitors block MHC-restricted antigen presentation in vivo. THE JOURNAL OF IMMUNOLOGY 2007; 179:5711-6. [PMID: 17947643 DOI: 10.4049/jimmunol.179.9.5711] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
APCs, like T cells, are affected by calcineurin inhibitors. In this study, we show that calcineurin inhibitors efficiently block MHC-restricted exogenous Ag presentation in vivo. Mice were injected with clinical doses of tacrolimus (FK-506) followed by soluble OVA, and dendritic cells (DCs) were isolated from lymph nodes and spleens. The efficacy of OVA peptide presentation by DCs was evaluated using OVA-specific CD8 and CD4 T cells. Tacrolimus inhibited both class I- and class II-restricted DC presentation of OVA to T cells. Tacrolimus also inhibited both class I- and class II-restricted presentation of OVA in peritoneal macrophages isolated from mice injected with tacrolimus followed by soluble OVA. Tacrolimus-treated peritoneal macrophages, however, were able to present synthetic OVA peptide, SIINFEKL. Inclusion of cyclosporine A to biodegradable microspheres containing OVA greatly reduced their capacity to induce OVA-specific CTL response in mice. These findings provide novel insight into the mode of action of calcineurin inhibitors and have important implications for clinical immunosuppression regimens.
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Affiliation(s)
- Young-Hee Lee
- College of Pharmacy, Chungbuk National University, Cheongju, South Korea
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26
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Cannon MJ, Davis JS, Pate JL. Expression of costimulatory molecules in the bovine corpus luteum. Reprod Biol Endocrinol 2007; 5:5. [PMID: 17266770 PMCID: PMC1800853 DOI: 10.1186/1477-7827-5-5] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2006] [Accepted: 01/31/2007] [Indexed: 01/30/2023] Open
Abstract
BACKGROUND Bovine luteal parenchymal cells express class II major histocompatibility complex (MHC) molecules and stimulate class II MHC-dependent activation of T cells in vitro. The ability of a class II MHC-expressing cell type to elicit a response from T cells in vivo is also dependent on expression of costimulatory molecules by the antigen presenting cell and delivery of a costimulatory signal to the T cell. Whether bovine luteal parenchymal cells express costimulatory molecules and can deliver the costimulatory signal is currently unknown. METHODS Bovine luteal tissue was collected during the early (day 5; day of estrus = day 0), mid (day 11-12), or late (day 18) luteal phase of the estrous cycle, and at 0, 0.5, 1, 4, 12 or 24 hours following administration of PGF2alpha to cows on day 10 of the estrous cycle. Northern analysis was used to measure CD80 or CD86 mRNA concentrations in luteal tissue samples. Mixed luteal parenchymal cell cultures and purified luteal endothelial cell cultures were prepared, and real-time RT-PCR was used to examine the presence of CD80 and CD86 mRNA in each culture type. Monoclonal antibodies to CD80 and CD86 were added to a mixed luteal parenchymal cell-T cell co-culture in vitro T cell proliferation assay to assess the functional significance of costimulatory molecules on activation of T lymphocytes by luteal parenchymal cells. RESULTS Northern analysis revealed CD80 and CD86 mRNAs in luteal tissue, with greatest steady-state concentrations at midcycle. CD80 and CD86 mRNAs were detected in mixed luteal parenchymal cell cultures, but only slight amounts of CD80 (and not CD86) mRNA were detected in cultures of luteal endothelial cells. Luteinizing hormone, PGF2alpha and TNF-alpha were without effect on concentrations of CD80 or CD86 mRNA in mixed luteal parenchymal cells cultures. Anti-CD80 or anti-CD86 monoclonal antibodies inhibited T cell proliferation in the in vitro T cell proliferation assay. CONCLUSION It can be concluded from this study that parenchymal cells within the bovine CL express functional costimulatory molecules that facilitate interactions between with T cells, and these components of the antigen presentation pathway are expressed maximally in the midcycle CL.
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Affiliation(s)
- Matthew J Cannon
- Department of Animal Sciences, The Ohio State University/Ohio Agricultural Research and Development Center, Wooster, Ohio 44691, USA
| | - John S Davis
- Olson Center for Women's Health, Department of Obstetrics and Gynecology, University of Nebraska Medical Center, Omaha, Nebraska 68198; OVAMC 983255 Nebraska Medical Center, Omaha, Nebraska 68198, USA
| | - Joy L Pate
- Department of Animal Sciences, The Ohio State University/Ohio Agricultural Research and Development Center, Wooster, Ohio 44691, USA
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27
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Fang M, Sigal LJ. Direct CD28 costimulation is required for CD8+ T cell-mediated resistance to an acute viral disease in a natural host. THE JOURNAL OF IMMUNOLOGY 2007; 177:8027-36. [PMID: 17114476 DOI: 10.4049/jimmunol.177.11.8027] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Previous studies have suggested that, differing from model Ags, viruses that replicate extensively in the host still induce normal CD8+ T cell responses in the absence of CD28 costimulation. Because these studies were performed with viruses that do not normally cause acute disease, an important remaining question is whether CD28 costimulation is required for CD8+ T cell-mediated resistance to widely replicating but pathogenic viruses. To address this question, we studied the role of CD28 costimulation in CD8+ T cell-mediated resistance to mousepox, a disease of the mouse caused by the natural mouse pathogen, the ectromelia virus (ECTV). C57BL/6 (B6) mice are naturally resistant to mousepox, partly due to a fast and strong CD8+ T cell response. We found that B6 mice deficient in CD28 (CD28 knockout (KO)) are highly susceptible to lethal mousepox during the early stages of ECTV infection but can be protected by immunization with the antigenically related vaccinia virus (VACV) or by adoptive transfer of CD28 KO anti-VACV memory CD8+ cells. Of interest, a thorough comparison of the CD8+ T cell responses to ECTV and VACV suggests that the main reason for the susceptibility of CD28 KO mice to mousepox is a reduced response at the early stages of infection. Thus, while in the absence of CD28 costimulation the end point strength of the T cell responses to nonpathogenic viruses may appear normal, CD28 costimulation increases the speed of the T cell response and is essential for resistance to a life-threatening acute viral disease.
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Affiliation(s)
- Min Fang
- Program on Viral Pathogenesis, Division of Basic Sciences, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111
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28
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Elson CO, Cong Y, Weaver CT. Alterations of T lymphocytes in inflammatory bowel diseases. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2006; 579:133-48. [PMID: 16620016 DOI: 10.1007/0-387-33778-4_9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/08/2023]
Affiliation(s)
- Charles O Elson
- Division of Gastroenterology and Hepatology, University of Alabama, Birmingham, Alabama, USA
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29
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Kotani M, Hirata K, Ogawa S, Habiro K, Ishida Y, Tanuma S, Horai R, Iwakura Y, Kishimoto H, Abe R. CD28-dependent differentiation into the effector/memory phenotype is essential for induction of arthritis in interleukin-1 receptor antagonist-deficient mice. ACTA ACUST UNITED AC 2006; 54:473-81. [PMID: 16453283 DOI: 10.1002/art.21769] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
OBJECTIVE Interleukin-1 receptor antagonist (IL-1Ra)-deficient mice on a BALB/c background spontaneously develop a chronic inflammatory polyarthropathy closely resembling that of rheumatoid arthritis in humans. To elucidate the role of CD28 costimulatory signals in the development of this disease, we studied IL-1Ra/CD28-double-deficient mice. METHODS We crossed IL-1Ra-deficient mice with CD28-deficient mice and observed the incidence and severity of arthritis. To investigate functions of IL-1Ra/CD28-double-deficient T cells, cells were stimulated with CD3 monoclonal antibody or allogeneic antigen-presenting cells (APCs) and their proliferative responses and levels of cytokine production were measured. RESULTS Disease severity was lower in IL-1Ra/CD28-double-deficient mice than in mice that were deficient only in IL-1Ra, although incidence of arthritis was not affected by the presence or absence of CD28. When pathogenic IL-1Ra-KO T cells were transferred into nude mice, severe arthritis developed. Even though T cells from double-deficient mice showed the same diminished proliferative capacity as was seen in T cells from CD28-single-deficient animals, nude mice into which double-deficient T cells were transferred never developed arthritis. CONCLUSION These findings indicate that IL-1Ra/CD28-double-deficient T cells can be activated by IL-1Ra-deficient activated APCs, resulting in induction of arthritis; however, these T cells did not induce the disease under normal conditions, because they did not differentiate into effector/memory phenotype.
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30
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Affiliation(s)
- Hong Jiang
- Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
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31
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Friedmann-Morvinski D, Eshhar Z. Adoptive immunotherapy of cancer using effector lymphocytes redirected with antibody specificity. ACTA ACUST UNITED AC 2006. [DOI: 10.1016/j.uct.2006.04.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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Wüthrich M, Warner T, Klein BS. CD28 is required for optimal induction, but not maintenance, of vaccine-induced immunity to Blastomyces dermatitidis. Infect Immun 2005; 73:7436-41. [PMID: 16239544 PMCID: PMC1273838 DOI: 10.1128/iai.73.11.7436-7441.2005] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
Cellular immunity mediated by T lymphocytes, in particular CD4+ and CD8+ type 1 cells, is the main defense against pathogenic fungi. Here, CD28-deficient (CD28-/-) mice were used to study the role of costimulation for the generation and maintenance of T-cell-mediated, type 1 cytokine-dependent mechanisms of vaccine immunity to Blastomyces dermatitidis infection. Disruption of CD28 costimulation reduced the number of type 1 CD4 and CD8 cells generated and impaired resistance to infection. Type 1 T-cell subsets generated in vaccinated CD28-/- mice were durable and protected mice for at least 3 months after vaccination. Our findings suggest that CD28 is required for the induction of optimal, protective T-cell responses to B. dermatitidis infection but may be dispensable for the maintenance of T-cell memory.
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Affiliation(s)
- Marcel Wüthrich
- University of Wisconsin Hospitals and Clinics, 600 Highland Ave., K4/444, Madison, WI 53792, USA.
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Kuo SH, Chen LT, Chen CL, Doong SL, Yeh KH, Wu MS, Mao TL, Hsu HC, Wang HP, Lin JT, Cheng AL. Expression of CD86 and increased infiltration of NK cells are associated with Helicobacter pylori-dependent state of early stage high-grade gastric MALT lymphoma. World J Gastroenterol 2005; 11:4357-4362. [PMID: 16038034 PMCID: PMC4434662 DOI: 10.3748/wjg.v11.i28.4357] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2004] [Revised: 12/03/2004] [Accepted: 12/08/2004] [Indexed: 02/06/2023] Open
Abstract
AIM A high percentage of early-stage high-grade gastric mucosa-associated lymphoid tissue (MALT) lymphomas remain Helicobacter pylori (H pylori)-dependent. However, unlike their low-grade counterparts, high-grade gastric MALT lymphomas may progress rapidly if unresponsive to H pylori eradication. It is mandatory to identify markers that may predict the H pylori-dependent status of these tumors. Proliferation of MALT lymphoma cells depends on cognate help and cell-to-cell contact of H pylori-specific intratumoral T-cells. To examine whether the expression of co-stimulatory marker CD86 (B7.2) and the infiltration of CD56 (+) natural killer (NK) cells can be useful markers to predict H pylori-dependent status of high-grade gastric MALT lymphoma. METHODS Lymphoma biopsies from 26 patients who had participated in a prospective study of H pylori-eradication for stage I(E) high-grade gastric MALT lymphomas were evaluated. Tumors that resolved to Wotherspoon grade II or less after H pylori eradication were classified as H pylori-dependent; others were classified as H pylori-independent. The infiltration of NK cells and the expression of CD86 in pre-treatment paraffin-embedded lymphoma tissues were determined by immunohistochemistry. RESULTS There were 16 H pylori-dependent and 10 H pylori-independent cases. CD86 expression was detected in 11 (68.8%) of 16 H pylori-dependent cases but in none of 10 H pylori-independent cases (P = 0.001). H pylori-dependent high-grade gastric MALT lymphomas contained significantly higher numbers of CD56 (+) NK cells than H pylori-independent cases (2.8+/-1.4% vs 1.1+/-0.8%; P = 0.003). CD86 positive MALT lymphomas also showed significantly increased infiltration of CD56 (+) NK cells compared to CD86-negative cases (2.9+/-1.1% vs 1.4+/-1.3%; P = 0.005). CONCLUSION These results suggest that the expression of co-stimulatory marker CD86 and the increased infiltration of NK cells are associated with H pylori-dependent state of early-stage high-grade gastric MALT lymphomas.
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MESH Headings
- Adult
- Aged
- Aged, 80 and over
- Antigens, CD/metabolism
- B7-2 Antigen
- Biomarkers/metabolism
- Female
- Helicobacter Infections/immunology
- Helicobacter Infections/pathology
- Helicobacter pylori
- Humans
- Killer Cells, Natural/immunology
- Killer Cells, Natural/metabolism
- Killer Cells, Natural/microbiology
- Lymphoma, B-Cell, Marginal Zone/immunology
- Lymphoma, B-Cell, Marginal Zone/microbiology
- Lymphoma, B-Cell, Marginal Zone/pathology
- Male
- Membrane Glycoproteins/metabolism
- Middle Aged
- Neoplasm Staging
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Affiliation(s)
- Sung-Hsin Kuo
- Department of Oncology, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei, Taiwan, China
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Lu J, Zhao J, Song Q, Cui ZY, Zhao GQ, Yang HY, Huang YT, Zhao JM, Dong ZM. Combination effect of human B7-2 and dentric cells vaccines in anti-esophageal cancer in vitro. Shijie Huaren Xiaohua Zazhi 2005; 13:1382-1385. [DOI: 10.11569/wcjd.v13.i12.1382] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
AIM: To investigate the roles of human B7-2 combined with dentric cell (DC) vaccine in inducing anti-tumor immunity against esophageal cancer in vitro.
METHODS: Human esophageal cancer cell line EC9706 was transfected with the vector of pEGFP-N3-B7-2 by lipofectamine method. The mononuclear cells (MNCs) were separated from cord blood by density gradient centrifugation (Ficall-Hypaque) and then were induced to differentiate by cell factors. On the 3rd day, EC9706 cytolysis antigen was added into the medium, in which DCs gradually matured and expressed special tumor antigen. After the matured DCs were co-cultured with autologous T cells derived from cord blood for 3 days, the T cells were activated to become tumor specific cytotoxic T lymphocytes (CTL). The inhibition of CTL on the transfected and untransfected EC9706 cells was detected by methyl thiazolyl tetrazolium (MTT) assay.
RESULTS: The EGFP-B7-2 fusion gene was expressed mainly on the membrane of EC9706 cells, which proved the transfection was successful. Mature DCs with tumor cytolysis antigene was able to activate naive T cells to become tumor specialized CTL, and the CTL had significant inhibitory effect or killing response on EC9706 cells transfected with pEGFP-N3-B7-2(F = 21.672,P = 0.000).
CONCLUSION: The human B7-2 combined with DC vaccine can induce significant killing response on esophageal cancer cell.
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Marckmann S, Wiesemann E, Hilse R, Trebst C, Stangel M, Windhagen A. Interferon-beta up-regulates the expression of co-stimulatory molecules CD80, CD86 and CD40 on monocytes: significance for treatment of multiple sclerosis. Clin Exp Immunol 2005; 138:499-506. [PMID: 15544628 PMCID: PMC1809242 DOI: 10.1111/j.1365-2249.2004.02624.x] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
Abstract
Interferon (IFN)-beta reduces the biological activity of multiple sclerosis (MS), a presumably T cell-mediated autoimmune disease of central nervous system (CNS) myelin. Co-stimulatory molecules are necessary for full T cell activation and differential expression of co-stimulatory molecules on antigen-presenting cells is thought to influence the type of effector T cell response (Th1/Th2). In this study we investigated the effects of IFN-beta on the expression of co-stimulatory molecules on lymphocytes and monocytes as a potential mechanism of action of IFN-beta in MS. Peripheral blood mononuclear cells (PBMCs) were stimulated with IFN-beta in vitro and expression of CD80, CD86, CD40 and HLA was examined by flow cytometry and reverse-transcription polymerase chain reaction. Whereas IFN-beta had no effect on the expression of these molecules on T and B lymphocytes there was a significant increase on monocytes. Correspondingly, the expression of mRNA increased after 6-18 h. This in vitro response was also observed in untreated MS patients and patients receiving treatment with IFN-beta. The increase of co-stimulatory molecules on monocytes was not mediated by interleukin (IL)-10. When IFN-beta-stimulated monocytes were used to stimulate autologous T cells an increased secretion of IL-13 was observed. In biopsies taken from IFN-beta-induced skin reactions after subcutaneous injection increased expression of CD80 mRNA was detected, indicating that IFN-beta also up-regulates this co-stimulatory molecule in vivo. These data provide the background for further studies of IFN-beta-induced changes of co-stimulatory molecules in MS patients.
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Affiliation(s)
- S Marckmann
- Department of Neurology, Medical School Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
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Biburger M, Weth R, Wels WS. A Novel Bispecific Tetravalent Antibody Fusion Protein to Target Costimulatory Activity for T-cell Activation to Tumor Cells Overexpressing ErbB2/HER2. J Mol Biol 2005; 346:1299-311. [PMID: 15713482 DOI: 10.1016/j.jmb.2004.12.052] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2004] [Revised: 12/21/2004] [Accepted: 12/22/2004] [Indexed: 11/20/2022]
Abstract
Persistent activation of T-lymphocytes requires two signals: one is initiated by T-cell receptor binding to antigenic peptide presented by MHC molecules. In addition, binding of the B7 family members CD80 or CD86 on professional antigen presenting cells to CD28 on T cells is considered to provide an important costimulatory signal. Activation without costimulation induces T-cell unresponsiveness or anergy. To selectively localize costimulatory activity to the surface of tumor cells and enhance activation of tumor-specific T cells, we have developed a novel molecular design for bispecific costimulatory proteins with antibody-like structure. Within a single polypeptide chain we have assembled the IgV-like, CD28-binding domain of human CD86 (CD86(111)) together with hinge, CH2 and CH3 domains of human IgG1, and the scFv(FRP5) antibody fragment which recognizes the ErbB2 (HER2) protooncogene present at high levels on the surface of many human tumor cells. Upon expression in the yeast Pichia pastoris, the resulting CD86(111)-IgG-scFv(FRP5) protein could be purified as a homodimeric, tetravalent molecule from culture supernatants using single-step affinity chromatography. Bispecific binding of the molecule to ErbB2 on the surface of tumor cells and to the B7 counter receptor CTLA-4 was demonstrated by FACS analysis. Potent costimulatory activity of chimeric CD86(111)-IgG-scFv(FRP5) was confirmed by its ability to stimulate the proliferation of primary human lymphocytes pre-activated by low concentrations of anti-CD3 antibody. Our results suggest that such multivalent soluble proteins which combine specific targeting to tumor cells with costimulatory activity may become useful tools to elicit and/or improve T-cell mediated, tumor-specific immune responses.
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Affiliation(s)
- Markus Biburger
- Chemotherapeutisches Forschungsinstitut Georg-Speyer-Haus, Paul-Ehrlich-Strasse 42-44, 60596 Frankfurt am Main, Germany
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Borkow G, Bentwich Z. Chronic immune activation associated with chronic helminthic and human immunodeficiency virus infections: role of hyporesponsiveness and anergy. Clin Microbiol Rev 2005; 17:1012-30, table of contents. [PMID: 15489359 PMCID: PMC523563 DOI: 10.1128/cmr.17.4.1012-1030.2004] [Citation(s) in RCA: 101] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
Chronic immune activation is one of the hallmarks of human immunodeficiency virus (HIV) infection. It is present also, with very similar characteristics, in very large human populations infested with helminthic infections. We have tried to review the studies addressing the changes in the immune profiles and responses of hosts infected with either one of these two chronic infections. Not surprisingly, several of the immune derangements and impairments seen in HIV infection, and considered by many to be the "specific" effects of HIV, can be found in helminth-infected but HIV-noninfected individuals and can thus be accounted for by the chronic immune activation itself. A less appreciated element in chronic immune activation is the immune suppression and anergy which it may generate. Both HIV and helminth infections represent this aspect in a very wide and illustrative way. Different degrees of anergy and immune hyporesponsiveness are present in these infections and probably have far-reaching effects on the ability of the host to cope with these and other infections. Furthermore, they may have important practical implications, especially with regard to protective vaccinations against AIDS, for populations chronically infected with helminths and therefore widely anergic. The current knowledge of the mechanisms responsible for the generation of anergy by chronic immune activation is thoroughly reviewed.
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Affiliation(s)
- Gadi Borkow
- Animal Scienes, Faculty of Agriculture, Hebrew University, Rehovot, Israel
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Nabeyama K, Yasunami Y, Toyofuku A, Nakano M, Satoh M, Matsuoka N, Ono J, Kamada M, Uede T, Todo S, Ikeda S. Beneficial Effects of Costimulatory Blockade with Anti-Inducible Costimulator Antibody in Conjunction with CTLA4Ig on Prevention of Islet Xenograft Rejection from Rat to Mouse. Transplantation 2004; 78:1590-6. [PMID: 15591946 DOI: 10.1097/01.tp.0000144054.46946.cf] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
BACKGROUND Costimulatory signals have been reported to play an important role in islet-xenograft rejection, although the precise mechanisms remain unknown. The aim of the present study was to determine a role of a novel costimulatory molecule, inducible costimulator (ICOS), in rat islet-xenograft rejection in conjunction with CTLA4Ig with respect to cellular as well as humoral immune responses. METHODS Isolated rat islets were transplanted into the liver of streptozotocin (180 mg/kg) induced diabetic mice. Cellular immune responses to islet xenografts, and productions of anti-rat antibody in mice were examined by flow cytometry (FACS) after transplantation. RESULTS Intrahepatic rat islet xenografts were rejected in mice within 8 days after transplantation. FACS analysis revealed an expansion of CD8(+) T cells in the liver as well as a production of anti-rat antibody in recipient mice in association with rejection. The treatment with anti-ICOS antibody in conjunction with CTLA4Ig produced a marked prolongation of islet-xenograft survival with neither expansion of CD8(+) T cells nor production of anti-rat antibody, whereas, in contrast, those treated with anti-ICOS antibody or CTLA4Ig alone did not have prolonged survival, and CD8(+) T cells were expanded. CONCLUSION These findings demonstrate that cellular rather than humoral immune responses are considered responsible for islet-xenograft rejection from rat to mouse and that the blockade of costimulatory signals with anti-ICOS antibody in conjunction with CTLA4Ig has a favorable effect on prevention of islet xenograft rejection.
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Affiliation(s)
- Kentaroh Nabeyama
- Department of Surgery I, Fukuoka University School of Medicine, 7-45-1, Nanakuma, Jonanku, Fukuoka 814-0180, Japan
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Wu Q, Jinde K, Endoh M, Sakai H. Clinical significance of costimulatory molecules CD80/CD86 expression in IgA nephropathy. Kidney Int 2004; 65:888-96. [PMID: 14871408 DOI: 10.1111/j.1523-1755.2004.00477.x] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
BACKGROUND IgA nephropathy (IgAN) is the most common form of human glomerulonephritis. Tubulointerstitial inflammation with infiltration of mononuclear cells plays an important role in the progression of IgAN. Activation of T cells requires costimulatory signals through binding of CD28 receptor with cognate ligands (CD80/CD86) located on antigen-presenting cells (APC). To assess the clinical significance of this regulatory pathway participation in the pathogenesis of IgAN, a comprehensive immunohistologic evaluation was conducted on renal tissue of IgAN in different phases of progressive injury. METHODS Thirty-three cases of IgAN and ten cases of non-IgA mesangial proliferative glomerulonephritis (PGN) with minor tissue damage as controls were investigated. Monoclonal antibodies were used to assess the expression of CD80, CD86, CD68, CD14, CD45RO, human leukocyte antigen-DR (HLA-DR), and intercellular adhesion molecule-1 (ICAM-1) in renal tissues. Clinical and expression data were compared at the time of renal biopsy. RESULTS CD80+ and CD86+ cells were observed more in IgAN patients with progressive renal injury than in mild cases and controls. CD80 was limited to tubular epithelial cells and was complemented by HLA-DR expression. CD86 was expressed in the glomerulus, periglomerular area, and peritubular interstitium. Activated T cells (CD45RO+), monocytes (CD14+), macrophages (CD68+), and CD86 showed similar distributions. Positive correlations were found between CD86+ cells and CD45RO, CD14, and CD68 positive cells and between CD80+ tubuli and peritubular interstitial CD45RO+ cells. The number of interstitial CD86 positive cells and the percentage of CD80+ tubuli were correlated with renal function. Most CD86+ cells were monocyte/macrophages. CONCLUSION This study suggested that CD80 and CD86 activate T cells in IgAN, CD80/CD86 expressions correlated with renal function at the time of renal biopsy, and monocyte/macrophages and tubular epithelial cells act as APC.
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Affiliation(s)
- Qiong Wu
- Department of Internal Medicine, School of Medicine, Tokai University, Isehara, Kanagawa, Japan.
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40
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Affiliation(s)
- Hong Jiang
- Department of Medicine and Pathology, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA
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Maio M, Coral S, Fratta E, Altomonte M, Sigalotti L. Epigenetic targets for immune intervention in human malignancies. Oncogene 2003; 22:6484-8. [PMID: 14528272 DOI: 10.1038/sj.onc.1206956] [Citation(s) in RCA: 54] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Emerging evidences suggest that epigenetic events associated with tumor development and progression, such as deregulated methylation of CpG dinucleotides and aberrant histone acetylation, may impair the immunogenic potential of cancer cells. In fact, DNA hypermethylation and/or histone deacetylation contribute to the absent or downregulated expression of different components of the 'tumor recognition complex' (i.e., HLA class I antigens, cancer/testis antigens and accessory/costimulatory molecules) in solid and hemopoietic human malignancies. However, pharmacologic agents that induce DNA hypomethylation or inhibit histone deacetylation can modify these epigenetic phenomena, restoring the defective expression of selected components of the 'tumor recognition complex' in cancer cells. These antigenic modifications positively modulate the immunogenicity and the immune recognition of cancer cells, making epigenetic drugs attractive agents to design new combined chemoimmunotherapeutic strategies for the treatment of cancer patients.
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Affiliation(s)
- Michele Maio
- Cancer Bioimmunotherapy Unit, Department of Medical Oncology, Centro di Riferimento Oncologico, Istituto di Ricovero e Cura a Carattere Scientifico, Aviano 33081, Italy.
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Abstract
Modulation of signal transduction pathways represents a promising approach for altering the biological behavior of hematopoetic malignancies. The cells of chronic lymphocytic leukemia were treated in vitro with CD40-ligand or IL-4 to explore their effects on survival and sensitivity to apoptosis induced by Fluda. The expression of G1 cell cycle regulatory proteins was also measured. Stimulation via CD40-CD40L resulted in increased viability, as did stimulation with IL-4. A combination of the two stimulators (CD40L plus IL-4) induced increased expression of cyclins D3 and E, pRb phosphorylation and downregulated p27. Cdk2 and Cdk4 activities were not detected. It seems that this combination induced also some progression in the cell cycle. Furthermore, Fluda-induced apoptosis was not prevented by CD40L, IL-4, or a combination of both agents, although a delay in the onset of apoptosis was observed. Taken together, these results support the view that CD40L and IL-4 sustain B-cell chronic lymphocytic leukemia (B-CLL) survival by different pathways and their synergistic action might induce cell cycle progression in B-CLL. The exposure of B-CLL to CD40L, IL-4 or both did not impair the sensitivity of B-CLL to Fluda. CD40L and IL-4 postponed apoptosis induced by Fluda, depending on a fashion of administration.
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Affiliation(s)
- Mira Grdisa
- Departement d'Hematologie et d'Oncologie Medicale, Hopital Hotel Dieu, Paris, France.
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Martínez-Escribano JA, Hernández-Caselles T, Campillo JA, Campos M, Frías JF, García-Alonso A, Alvarez-López MR. Changes in the number of CD80(+), CD86(+), and CD28(+) peripheral blood lymphocytes have prognostic value in melanoma patients. Hum Immunol 2003; 64:796-801. [PMID: 12878358 DOI: 10.1016/s0198-8859(03)00122-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Our aim was to evaluate whether the number of circulating lymphocytes expressing costimulatory molecules can be associated with melanoma prognosis. We determined the concentration of peripheral blood lymphocytes, which expressed the CD80/CD86 or CD28/CTLA-4 molecules, in 38 patients with cutaneous melanoma and 27 controls. The number of each cell subset was compared between patients and controls, as well as between groups of patients stratified according to Breslow thickness of the primary tumor (< or = 2 mm vs > 2 mm) or to survival after 3 years. The concentration of circulating lymphocytes expressing the CD80/CD86 molecules was not significantly different between patients and controls. There was a lower number of CD3(+)CD8(+)CD28(+) cells, as well as a higher CD3(+)CD8(+)/CD3(+)CD8(+)CD28(+) cell ratio, in melanoma patients than in controls. Melanoma patients with thinner tumors and those surviving revealed an increase of CD19(+)CD80(+) and CD19(+)CD80(+)CD86(+) cells, as well as a higher concentration of CD3(+)CD4(+)CD28(+) cells. CD80(+) B cells and a low CD8 suppressor/cytolytic cell ratio correlate with a good prognosis in melanoma. Our findings support our conclusion that CD80(+) B cells may be important antigen presenting cells that can contribute to an antimelanoma immune response and are candidates to be monitored in melanoma patients.
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Pietrella D, Fries B, Lupo P, Bistoni F, Casadevall A, Vecchiarelli A. Phenotypic switching of Cryptococcus neoformans can influence the outcome of the human immune response. Cell Microbiol 2003; 5:513-22. [PMID: 12864811 DOI: 10.1046/j.1462-5822.2003.00297.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
The human pathogenic fungus Cryptococcus neoformans exhibits the phenomenon of phenotypic switching, a process that generates variant colonies that can differ in morphology, virulence and other characteristics such as capsular glucuronoxylomannan (GXM) size and structure. A previous study established that mucoid colony (MC) variants of C. neoformans were more virulent and elicited a different inflammatory response than smooth colony (SM) variants. In this study, we investigated the interaction of cells from MC and SM variants and their respective GXMs with human T cells and monocytes. Specifically, we measured CD40, CD80 and CD86 expression, lymphoproliferation and interleukin (IL)-4, IL-10, interferon (IFN)-gamma and IL-12Rbeta2 expression in the presence and absence of variant cells and their GXMs. For some immune parameters, both MC and SM strains produced similar results, in particular no differences were observed in IL-4 induction. However, for other critical parameters, including CD86 expression, lymphoproliferation and IL-10 production, the MC variant had effects that can be expected to impair the immune response. Hence, a single C. neoformans strain can elicit several different immune responses depending on the colony type expressed, and this is unlikely to be accounted for by differences in phagocytosis only. The results provide a potential explanation for the higher virulence of the MC variant based on the concept that these cells inhibit the development of a vigorous immune response. Furthermore, the results suggest a mechanism by which phenotypic switching can generate variants able to evade the immune response.
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Affiliation(s)
- Donatella Pietrella
- Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Italy
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Abstract
T-cell receptor-mediated T-cell activation requires cosimulation signal, which can be provided by B7-1 molecule. Our previous study demonstrated that the coexpression of a covalent peptide/major histocompatibility complex class II molecule complex and costimulatory molecule B7-1 by recombinant adenovirus leads to synergy in peptide-specific T-cell activation. However, the viral antigen-specific T-cell activation is not enhanced by B7-1 expressed by the adenovirus. To verify the differential T cell activation by B7-1 and investigate its underlying mechanisms, we constructed an adenovirus coexpressing a covalent complex of hen egg lysozyme peptide/I-Ak (HEL46-61/I-Ak) and B7-1 in the present study. In vivo studies revealed that HEL46-61-specific T-cell response, but not viral antigen-specific T-cell response, was enhanced by B7-1 expression mediated by the adenovirus, suggesting that exogenous B7-1 expression may regulate T-cell response to these two different antigens through distinct mechanisms. Furthermore, our results revealed that antigen-presenting cells were not susceptible to adenovirus infection in vivo. Based on these findings, the possible mechanism of differential B7-1 costimulation on peptide-specific and viral antigen-specific T-cell activation is discussed.
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Affiliation(s)
- Wei Li
- Department of Ophthalmology, University of Miami School of Medicine, FL, USA.
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Wu Q, Jinde K, Endoh M, Sakai H. Costimulatory molecules CD80 and CD86 in human crescentic glomerulonephritis. Am J Kidney Dis 2003; 41:950-61. [PMID: 12722029 DOI: 10.1016/s0272-6386(03)00192-6] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
BACKGROUND CD80 and CD86, cell-surface molecules found only on antigen-presenting cells (APCs), are required for activation of CD4-postitve (CD4+) T cells by interaction with CD28/cytotoxic T-lymphocyte-associated antigen 4 on T cells. The roles of these molecules in human glomerulonephritis (GN) presently are unknown. METHODS Twelve cases of crescentic GN, thought to be a T helper cell-directed delayed-type hypersensitivity-like injury, and 10 controls with non-immunoglobulin A proliferative GN were used. Expression of CD80, CD86, CD4, CD14, CD68, HLA-DR, and intercellular adhesion molecule-1 was investigated in renal tissues using monoclonal antibodies and compared with clinical data at the time of renal biopsy. RESULTS CD80+ and CD86+ cells were observed significantly more in crescentic GN than in controls. CD86 was expressed in the glomerulus and interstitium, especially in the crescent, and adhesion to Bowman's capsule and periglomerular areas corresponding to these changes. Tubular epithelial cells showed no CD86 expression, but they expressed CD80, and some of them expressed HLA-DR. CD4, CD14, CD68, and CD86 showed similar distribution patterns. Positive correlations were found between CD86+ cells and CD4+, CD14+, and CD68+ cells. The number of interstitial CD86+ cells correlated with deterioration of renal function. Most CD86+ cells were monocyte/macrophages. CONCLUSION This study suggests that the costimulatory molecules CD80 and CD86 have different expressions in human crescentic GN, and CD86 is concerned with crescent formation and CD4+ T-cell accumulations. The majority of APCs are macrophages, and tubular cells also can act as APCs.
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Affiliation(s)
- Qiong Wu
- Department of Internal Medicine, School of Medicine, Tokai University, Isehara, Kanagawa, Japan.
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Matsumoto A, Seki YI, Watanabe R, Hayashi K, Johnston JA, Harada Y, Abe R, Yoshimura A, Kubo M. A role of suppressor of cytokine signaling 3 (SOCS3/CIS3/SSI3) in CD28-mediated interleukin 2 production. J Exp Med 2003; 197:425-36. [PMID: 12591901 PMCID: PMC2193868 DOI: 10.1084/jem.20020939] [Citation(s) in RCA: 65] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Suppressor of cytokine signaling (SOCS)3 has been characterized as a negative feedback regulator in cytokine-mediated Janus kinase signal transducer and activator of transcription signaling. However, this study shows that T cells from transgenic mice expressing SOCS3 exhibit a significant reduction in interleukin (IL)-2 production induced by T cell receptor cross-linking when T cells are costimulated with CD28. Decreased protein expression in SOCS3(+/-) mice enhanced CD28-mediated IL-2 production, clearly indicating the correlation between expression level of SOCS3 and IL-2 production ability. The SOCS3 protein interacted with phosphorylated CD28 through its SH2 domain but not the kinase inhibitory region. In addition, a point mutation in the SOCS3 SH2 domain attenuated the inhibition of CD28 function in IL-2 promoter activation. Committed T helper (Th)2 cells exclusively expressed SOCS3 and production of Th2 cytokines, such as IL-4 and IL-5, was much less dependent on CD28 costimulation compared with interferon gamma and IL-2 production in Th1 cells. Consistent with this notion, the expression level of SOCS3 in early T cell activation influenced the ability of IL-2 production induced by CD28 costimulation. Therefore, the SOCS3 may play an alternative role in prohibiting excessive progression of CD28-mediated IL-2 production.
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Affiliation(s)
- Akira Matsumoto
- Research Institute for Biological Sciences, Tokyo University of Science, Chiba 278-0022, Japan
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48
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Planelles L, Thomas MC, Marañón C, Morell M, López MC. Differential CD86 and CD40 co-stimulatory molecules and cytokine expression pattern induced by Trypanosoma cruzi in APCs from resistant or susceptible mice. Clin Exp Immunol 2003; 131:41-7. [PMID: 12519384 PMCID: PMC1808596 DOI: 10.1046/j.1365-2249.2003.02022.x] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Differential aspects of the host immune response generated by Trypanosoma cruzi infection were examined in two different mouse strains, BALB/c (haplotype H2-Kd) which does not overcome the acute phase of the infection and C57BL/6 (haplotype H2-Kb) which survives to the acute phase. After infection an increase in CD3+ T cells was observed in both mouse strains in the peritoneal cavity. However, while the CD3+ T cells from the BALB/c mice showed an increase in the IL-4 cytokine expression level, the same type of cells from the C57BL/6 mice showed an increase in IFN-gamma expression. In addition, only the macrophages from the C57BL/6 mice were activated secreting IL-12 and TNF-alpha and producing, moreover, high levels of nitrites. It was observed that also after parasite infection the expression of macrophage and dendritic cells CD40 and CD86 co-stimulation molecules from the spleen were diminished in BALB/c but not in C57BL/6 mice. In correlation with this observation the macrophages from the spleen of infected BALB/c mice secreted lower concentrations of nitrites than the C57BL/6 mouse cells. Also, the spleen dendritic cells from infected BALB/c mice had a small potential to present alloantigens in contrast to that observed in the infected C57BL/6 mouse cells.
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Affiliation(s)
- L Planelles
- Departamento de Biología Molecular, Instituto de Parasitología y Biomedicina López Neyra, CSIC, Granada, Spain
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49
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Derweesh IH, Tannenbaum CS, Rayman PA, Finke JH. Mechanisms of immune dysfunction in renal cell carcinoma. Cancer Treat Res 2003; 116:29-51. [PMID: 14650824 DOI: 10.1007/978-1-4615-0451-1_2] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/27/2023]
Affiliation(s)
- Ithaar H Derweesh
- Department of Immunology, Lerner Research Institute, Glickman Urological Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA
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50
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Myers KA, Ryan MG, Stern PL, Shaw DM, Embleton MJ, Kingsman SM, Carroll MW. Targeting immune effector molecules to human tumor cells through genetic delivery of 5T4-specific scFv fusion proteins. Cancer Gene Ther 2002; 9:884-96. [PMID: 12386827 DOI: 10.1038/sj.cgt.7700513] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2002] [Indexed: 11/09/2022]
Abstract
Although several clinical trials have shown beneficial effects by targeting tumor-associated antigens (TAAs) with monoclonal antibodies, a number of issues, including poor penetration of the tumor mass and human antimouse antibody responses, remain. The use of recombinant single-chain Fv (scFv) fragments has the potential to address these and other issues while allowing the addition of different effector functions. To develop therapeutic strategies that recruit both humoral and cellular arms of the immune response, we have constructed chimeric proteins linking either the human IgG1 Fc domain or the extracellular domain of murine B7.1 to a scFv specific for the oncofetal glycoprotein, 5T4. This TAA is expressed by a wide variety of carcinomas and is associated with metastasis and poorer clinical outcome. We have engineered retroviral constructs that produce fusion proteins able to interact simultaneously with both 5T4-positive cells and with the receptor/ligands of the immune effector moieties. Genetic delivery through a murine leukemia virus vector to 5T4-positive tumor cells results in the secreted scFv fusion protein binding to the cell surface. Furthermore, the scFv-HIgG1 fusion protein is able to direct lysis of 5T4-expressing human tumor cell lines through antibody-dependent cell cytotoxicity, indicating its potential as a gene therapy for human cancers.
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Affiliation(s)
- Kevin A Myers
- Oxford BioMedica (UK) Ltd., Medawar Centre, Oxford Science Park, UK
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