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1
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Chamseddine I, Kambara M, Bhatt P, Pilon-Thomas S, Rejniak KA. Optimizing the Efficacy of Vaccine-Induced Immunotherapy in Melanomas. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.01.06.631283. [PMID: 39829889 PMCID: PMC11741369 DOI: 10.1101/2025.01.06.631283] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 01/22/2025]
Abstract
Cancer therapeutic vaccines are used to strengthen a patient's own immune system by amplifying existing immune responses. Intralesional administration of the bacteria-based emm55 vaccine together with the PD1 checkpoint inhibitor produced a strong anti-tumor effect against the B16 melanoma murine model. However, it is not trivial to design an optimal order and frequency of injections for combination therapies. Here, we developed a coupled ordinary differential equations model calibrated to experimental data and used the mesh adaptive direct search method to optimize the treatment protocols of the emm55 vaccine and anti-PD1 combined therapy. This method determined that early consecutive vaccine injections combined with distributed anti-PD1 injections of decreasing separation time yielded the best tumor size reduction. The optimized protocols led to a twofold decrease in tumor area for the vaccine-alone treatment, and a fourfold decrease for the combined therapy. Our results reveal the tumor subpopulation dynamics in the optimal treatment condition, defining the path for efficacious treatment design. Similar computational frameworks can be applied to other tumors and other combination therapies to generate experimentally testable hypotheses in a fairly unrestricted and inexpensive setting.
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Affiliation(s)
- Ibrahim Chamseddine
- Department of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, United States
| | - Manoj Kambara
- High-School Internship Program at Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, United States
| | - Priya Bhatt
- High-School Internship Program at Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, United States
| | - Shari Pilon-Thomas
- Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, United States
| | - Katarzyna A Rejniak
- Department of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, United States
- Department of Oncologic Sciences, Morsani College of Medicine, University of South Florida, Tampa, FL, United States
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2
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Sheikhlary S, Lopez DH, Moghimi S, Sun B. Recent Findings on Therapeutic Cancer Vaccines: An Updated Review. Biomolecules 2024; 14:503. [PMID: 38672519 PMCID: PMC11048403 DOI: 10.3390/biom14040503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Revised: 04/06/2024] [Accepted: 04/16/2024] [Indexed: 04/28/2024] Open
Abstract
Cancer remains one of the global leading causes of death and various vaccines have been developed over the years against it, including cell-based, nucleic acid-based, and viral-based cancer vaccines. Although many vaccines have been effective in in vivo and clinical studies and some have been FDA-approved, there are major limitations to overcome: (1) developing one universal vaccine for a specific cancer is difficult, as tumors with different antigens are different for different individuals, (2) the tumor antigens may be similar to the body's own antigens, and (3) there is the possibility of cancer recurrence. Therefore, developing personalized cancer vaccines with the ability to distinguish between the tumor and the body's antigens is indispensable. This paper provides a comprehensive review of different types of cancer vaccines and highlights important factors necessary for developing efficient cancer vaccines. Moreover, the application of other technologies in cancer therapy is discussed. Finally, several insights and conclusions are presented, such as the possibility of using cold plasma and cancer stem cells in developing future cancer vaccines, to tackle the major limitations in the cancer vaccine developmental process.
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Affiliation(s)
- Sara Sheikhlary
- Department of Biomedical Engineering, College of Engineering, The University of Arizona, Tucson, AZ 85721, USA
| | - David Humberto Lopez
- Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, AZ 85721, USA; (D.H.L.); (S.M.)
| | - Sophia Moghimi
- Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, AZ 85721, USA; (D.H.L.); (S.M.)
| | - Bo Sun
- Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, AZ 85721, USA; (D.H.L.); (S.M.)
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3
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Russi RC, del Balzo D, Reidel IG, Alonso Bivou M, Flor N, Lujan A, Sanchez D, Damiani MT, Veaute C. Evaluation of three formulations based on Polymorphic membrane protein D in mice infected with Chlamydia trachomatis. Front Immunol 2023; 14:1267684. [PMID: 38045697 PMCID: PMC10690417 DOI: 10.3389/fimmu.2023.1267684] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Accepted: 10/23/2023] [Indexed: 12/05/2023] Open
Abstract
The significant impact of Chlamydia trachomatis(Ct) infections worldwide highlights the need to develop a prophylactic vaccine that elicits effective immunity and protects the host from the immunopathological effects of Ct infection. The aim of this study was to evaluate a vaccine based on a fragment of the Polymorphic membrane protein D (FPmpD) of C. trachomatis as an immunogen using a heterologous DNA prime-protein boost strategy in female mice Three different formulations were evaluated as protein boost: free recombinant FPmpD (rFPmpD) or rFPmpD formulated with a liposomal adjuvant alternatively supplemented with CpG or a cationic gemini lipopeptide as immunostimulants. The three candidates induced an increase in the cervicovaginal and systemic titers of anti-rFPmpD antibodies in two strains of mice (BALB/c and C57BL/6), with no evidence of fertility alterations. The three formulations induced a rapid and robust humoral immune response upon the Ct challenge. However, the booster with free rFPmpD more efficiently reduced the shedding of infective Ct and prevented the development of immunopathology. The formulations containing adjuvant induced a strong inflammatory reaction in the uterine tissue. Hence, the prime-boost strategy with the adjuvant-free FPmpD vaccine formulation might constitute a promissory candidate to prevent C. trachomatis intravaginal infection.
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Affiliation(s)
- Romina Cecilia Russi
- Laboratorio de Bioquímica e Inmunidad, Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Instituto de Medicina y Biología Experimental de Cuyo, Consejo Nacional de Investigaciones Científicas y Técnicas (IMBECUCONICET), Universidad Nacional de Cuyo, Mendoza, Argentina
- Experimental Immunology Laboratory, School of Biochemistry and Biological Sciences, National University of Litoral, Ciudad Universitaria, Santa Fe, Argentina
| | - Diego del Balzo
- Laboratorio de Bioquímica e Inmunidad, Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Instituto de Medicina y Biología Experimental de Cuyo, Consejo Nacional de Investigaciones Científicas y Técnicas (IMBECUCONICET), Universidad Nacional de Cuyo, Mendoza, Argentina
| | - Ivana Gabriela Reidel
- Experimental Immunology Laboratory, School of Biochemistry and Biological Sciences, National University of Litoral, Ciudad Universitaria, Santa Fe, Argentina
- Department of Immuno-Oncology, Beckman Research Institute of City of Hope, Duarte, CA, United States
| | - Mariano Alonso Bivou
- Laboratorio de Bioquímica e Inmunidad, Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Instituto de Medicina y Biología Experimental de Cuyo, Consejo Nacional de Investigaciones Científicas y Técnicas (IMBECUCONICET), Universidad Nacional de Cuyo, Mendoza, Argentina
| | - Noelia Flor
- Experimental Immunology Laboratory, School of Biochemistry and Biological Sciences, National University of Litoral, Ciudad Universitaria, Santa Fe, Argentina
| | - Agustín Lujan
- Laboratorio de Bioquímica e Inmunidad, Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Instituto de Medicina y Biología Experimental de Cuyo, Consejo Nacional de Investigaciones Científicas y Técnicas (IMBECUCONICET), Universidad Nacional de Cuyo, Mendoza, Argentina
| | - Diego Sanchez
- Laboratorio de Bioquímica e Inmunidad, Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Instituto de Medicina y Biología Experimental de Cuyo, Consejo Nacional de Investigaciones Científicas y Técnicas (IMBECUCONICET), Universidad Nacional de Cuyo, Mendoza, Argentina
| | - María Teresa Damiani
- Laboratorio de Bioquímica e Inmunidad, Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Instituto de Medicina y Biología Experimental de Cuyo, Consejo Nacional de Investigaciones Científicas y Técnicas (IMBECUCONICET), Universidad Nacional de Cuyo, Mendoza, Argentina
| | - Carolina Veaute
- Experimental Immunology Laboratory, School of Biochemistry and Biological Sciences, National University of Litoral, Ciudad Universitaria, Santa Fe, Argentina
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Huang Z, Callmann CE, Wang S, Vasher MK, Evangelopoulos M, Petrosko SH, Mirkin CA. Rational Vaccinology: Harnessing Nanoscale Chemical Design for Cancer Immunotherapy. ACS CENTRAL SCIENCE 2022; 8:692-704. [PMID: 35756370 PMCID: PMC9228553 DOI: 10.1021/acscentsci.2c00227] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Indexed: 05/12/2023]
Abstract
Cancer immunotherapy is a powerful treatment strategy that mobilizes the immune system to fight disease. Cancer vaccination is one form of cancer immunotherapy, where spatiotemporal control of the delivery of tumor-specific antigens, adjuvants, and/or cytokines has been key to successfully activating the immune system. Nanoscale materials that take advantage of chemistry to control the nanoscale structural arrangement, composition, and release of immunostimulatory components have shown significant promise in this regard. In this Outlook, we examine how the nanoscale structure, chemistry, and composition of immunostimulatory compounds can be modulated to maximize immune response and mitigate off-target effects, focusing on spherical nucleic acids as a model system. Furthermore, we emphasize how chemistry and materials science are driving the rational design and development of next-generation cancer vaccines. Finally, we identify gaps in the field that should be addressed moving forward and outline future directions to galvanize researchers from multiple disciplines to help realize the full potential of this form of cancer immunotherapy through chemistry and rational vaccinology.
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Affiliation(s)
- Ziyin Huang
- Department
of Materials Science and Engineering, International Institute for Nanotechnology, Department of Chemistry, Interdisciplinary
Biological Sciences Graduate Program, andDepartment of Biomedical Engineering, Northwestern University, Evanston, Illinois 60208, United States
| | - Cassandra E. Callmann
- Department
of Materials Science and Engineering, International Institute for Nanotechnology, Department of Chemistry, Interdisciplinary
Biological Sciences Graduate Program, andDepartment of Biomedical Engineering, Northwestern University, Evanston, Illinois 60208, United States
| | - Shuya Wang
- Department
of Materials Science and Engineering, International Institute for Nanotechnology, Department of Chemistry, Interdisciplinary
Biological Sciences Graduate Program, andDepartment of Biomedical Engineering, Northwestern University, Evanston, Illinois 60208, United States
| | - Matthew K. Vasher
- Department
of Materials Science and Engineering, International Institute for Nanotechnology, Department of Chemistry, Interdisciplinary
Biological Sciences Graduate Program, andDepartment of Biomedical Engineering, Northwestern University, Evanston, Illinois 60208, United States
| | - Michael Evangelopoulos
- Department
of Materials Science and Engineering, International Institute for Nanotechnology, Department of Chemistry, Interdisciplinary
Biological Sciences Graduate Program, andDepartment of Biomedical Engineering, Northwestern University, Evanston, Illinois 60208, United States
| | - Sarah Hurst Petrosko
- Department
of Materials Science and Engineering, International Institute for Nanotechnology, Department of Chemistry, Interdisciplinary
Biological Sciences Graduate Program, andDepartment of Biomedical Engineering, Northwestern University, Evanston, Illinois 60208, United States
| | - Chad A. Mirkin
- Department
of Materials Science and Engineering, International Institute for Nanotechnology, Department of Chemistry, Interdisciplinary
Biological Sciences Graduate Program, andDepartment of Biomedical Engineering, Northwestern University, Evanston, Illinois 60208, United States
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5
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Islam A, Tom VJ. The use of viral vectors to promote repair after spinal cord injury. Exp Neurol 2022; 354:114102. [PMID: 35513025 DOI: 10.1016/j.expneurol.2022.114102] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 04/21/2022] [Accepted: 04/27/2022] [Indexed: 11/16/2022]
Abstract
Spinal cord injury (SCI) is a devastating event that can permanently disrupt multiple modalities. Unfortunately, the combination of the inhibitory environment at a central nervous system (CNS) injury site and the diminished intrinsic capacity of adult axons for growth results in the failure for robust axonal regeneration, limiting the ability for repair. Delivering genetic material that can either positively or negatively modulate gene expression has the potential to counter the obstacles that hinder axon growth within the spinal cord after injury. A popular gene therapy method is to deliver the genetic material using viral vectors. There are considerations when deciding on a viral vector approach for a particular application, including the type of vector, as well as serotypes, and promoters. In this review, we will discuss some of the aspects to consider when utilizing a viral vector approach to as a therapy for SCI. Additionally, we will discuss some recent applications of gene therapy to target extrinsic and/or intrinsic barriers to promote axon regeneration after SCI in preclinical models. While still in early stages, this approach has potential to treat those living with SCI.
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Affiliation(s)
- Ashraful Islam
- Drexel University College of Medicine, Department of Neurobiology and Anatomy, Marion Murray Spinal Cord Research Center, Philadelphia, PA, USA
| | - Veronica J Tom
- Drexel University College of Medicine, Department of Neurobiology and Anatomy, Marion Murray Spinal Cord Research Center, Philadelphia, PA, USA.
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6
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Watanabe T. Approaches of the Innate Immune System to Ameliorate Adaptive Immunotherapy for B-Cell Non-Hodgkin Lymphoma in Their Microenvironment. Cancers (Basel) 2021; 14:cancers14010141. [PMID: 35008305 PMCID: PMC8750340 DOI: 10.3390/cancers14010141] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 12/14/2021] [Accepted: 12/23/2021] [Indexed: 12/21/2022] Open
Abstract
A dominant paradigm being developed in immunotherapy for hematologic malignancies is of adaptive immunotherapy that involves chimeric antigen receptor (CAR) T cells and bispecific T-cell engagers. CAR T-cell therapy has yielded results that surpass those of the existing salvage immunochemotherapy for patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) after first-line immunochemotherapy, while offering a therapeutic option for patients with follicular lymphoma (FL) and mantle cell lymphoma (MCL). However, the role of the innate immune system has been shown to prolong CAR T-cell persistence. Cluster of differentiation (CD) 47-blocking antibodies, which are a promising therapeutic armamentarium for DLBCL, are novel innate immune checkpoint inhibitors that allow macrophages to phagocytose tumor cells. Intratumoral Toll-like receptor 9 agonist CpG oligodeoxynucleotide plays a pivotal role in FL, and vaccination may be required in MCL. Additionally, local stimulator of interferon gene agonists, which induce a systemic anti-lymphoma CD8+ T-cell response, and the costimulatory molecule 4-1BB/CD137 or OX40/CD134 agonistic antibodies represent attractive agents for dendritic cell activations, which subsequently, facilitates initiation of productive T-cell priming and NK cells. This review describes the exploitation of approaches that trigger innate immune activation for adaptive immune cells to operate maximally in the tumor microenvironment of these lymphomas.
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Affiliation(s)
- Takashi Watanabe
- Department of Personalized Cancer Immunotherapy, Mie University Graduate School of Medicine, 2-174, Edobashi, Tsu City 514-8507, Japan
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7
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Anderluh M, Berti F, Bzducha-Wróbel A, Chiodo F, Colombo C, Compostella F, Durlik K, Ferhati X, Holmdahl R, Jovanovic D, Kaca W, Lay L, Marinovic-Cincovic M, Marradi M, Ozil M, Polito L, Reina JJ, Reis CA, Sackstein R, Silipo A, Švajger U, Vaněk O, Yamamoto F, Richichi B, van Vliet SJ. Recent advances on smart glycoconjugate vaccines in infections and cancer. FEBS J 2021; 289:4251-4303. [PMID: 33934527 PMCID: PMC9542079 DOI: 10.1111/febs.15909] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 04/09/2021] [Accepted: 04/30/2021] [Indexed: 01/01/2023]
Abstract
Vaccination is one of the greatest achievements in biomedical research preventing death and morbidity in many infectious diseases through the induction of pathogen-specific humoral and cellular immune responses. Currently, no effective vaccines are available for pathogens with a highly variable antigenic load, such as the human immunodeficiency virus or to induce cellular T-cell immunity in the fight against cancer. The recent SARS-CoV-2 outbreak has reinforced the relevance of designing smart therapeutic vaccine modalities to ensure public health. Indeed, academic and private companies have ongoing joint efforts to develop novel vaccine prototypes for this virus. Many pathogens are covered by a dense glycan-coat, which form an attractive target for vaccine development. Moreover, many tumor types are characterized by altered glycosylation profiles that are known as "tumor-associated carbohydrate antigens". Unfortunately, glycans do not provoke a vigorous immune response and generally serve as T-cell-independent antigens, not eliciting protective immunoglobulin G responses nor inducing immunological memory. A close and continuous crosstalk between glycochemists and glycoimmunologists is essential for the successful development of efficient immune modulators. It is clear that this is a key point for the discovery of novel approaches, which could significantly improve our understanding of the immune system. In this review, we discuss the latest advancements in development of vaccines against glycan epitopes to gain selective immune responses and to provide an overview on the role of different immunogenic constructs in improving glycovaccine efficacy.
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Affiliation(s)
- Marko Anderluh
- Faculty of Pharmacy, Faculty of Pharmacy, Chair of Pharmaceutical Chemistry, University of Ljubljana, Slovenia
| | | | - Anna Bzducha-Wróbel
- Department of Biotechnology and Food Microbiology, Warsaw University of Life Sciences-SGGW, Warszawa, Poland
| | - Fabrizio Chiodo
- Department of Molecular Cell Biology and Immunology, Cancer Center Amsterdam, Amsterdam Infection and Immunity Institute, Amsterdam UMC, Vrije Universiteit Amsterdam, The Netherlands.,Institute of Biomolecular Chemistry (ICB), Italian National Research Council (CNR), Pozzuoli, Italy
| | - Cinzia Colombo
- Department of Chemistry and CRC Materiali Polimerici (LaMPo), University of Milan, Italy
| | - Federica Compostella
- Department of Medical Biotechnology and Translational Medicine, University of Milan, Milano, Italy
| | - Katarzyna Durlik
- Department of Microbiology and Parasitology, Jan Kochanowski University, Kielce, Poland
| | - Xhenti Ferhati
- Department of Chemistry 'Ugo Schiff', University of Florence, Sesto Fiorentino, Italy
| | - Rikard Holmdahl
- Division of Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden
| | - Dragana Jovanovic
- Vinča Institute of Nuclear Sciences - National Institute of thе Republic of Serbia, University of Belgrade, Serbia
| | - Wieslaw Kaca
- Department of Microbiology and Parasitology, Jan Kochanowski University, Kielce, Poland
| | - Luigi Lay
- Department of Chemistry and CRC Materiali Polimerici (LaMPo), University of Milan, Italy
| | - Milena Marinovic-Cincovic
- Vinča Institute of Nuclear Sciences - National Institute of thе Republic of Serbia, University of Belgrade, Serbia
| | - Marco Marradi
- Department of Chemistry 'Ugo Schiff', University of Florence, Sesto Fiorentino, Italy
| | - Musa Ozil
- Faculty of Arts and Sciences, Department of Chemistry, Recep Tayyip Erdogan University, Rize, Turkey
| | - Laura Polito
- National Research Council, CNR-SCITEC, Milan, Italy
| | - Josè Juan Reina
- Departamento de Química Orgánica, Universidad de Málaga-IBIMA, Spain.,Andalusian Centre for Nanomedicine and Biotechnology-BIONAND, Parque Tecnológico de Andalucía, Málaga, Spain
| | - Celso A Reis
- I3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal.,IPATIMUP-Institute of Molecular Pathology and Immunology, University of Porto, Portugal.,Instituto de Ciências Biomédicas Abel Salazar, University of Porto, Portugal
| | - Robert Sackstein
- Department of Translational Medicine, Translational Glycobiology Institute, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA
| | - Alba Silipo
- Department of Chemical Sciences, University of Naples Federico II, Complesso Universitario Monte Sant'Angelo, Napoli, Italy
| | - Urban Švajger
- Blood Transfusion Center of Slovenia, Ljubljana, Slovenia
| | - Ondřej Vaněk
- Department of Biochemistry, Faculty of Science, Charles University, Prague, Czech Republic
| | - Fumiichiro Yamamoto
- Immunohematology & Glycobiology Laboratory, Josep Carreras Leukaemia Research Institute, Badalona, Spain
| | - Barbara Richichi
- Department of Chemistry 'Ugo Schiff', University of Florence, Sesto Fiorentino, Italy
| | - Sandra J van Vliet
- Department of Molecular Cell Biology and Immunology, Cancer Center Amsterdam, Amsterdam Infection and Immunity Institute, Amsterdam UMC, Vrije Universiteit Amsterdam, The Netherlands
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8
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Klebe M, Olbert PJ, Hofmann R, Barth PJ, Hegele A. [CpG-ODN instillation boosts ICAM-1 expression in an orthotopic murine UCC model: immunohistochemical evaluation of the local response to immunostimulatory DNA]. Aktuelle Urol 2021. [PMID: 33853160 DOI: 10.1055/a-1268-2069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
BACKGROUND Immunostimulatory CpG oligodeoxynucleotides (CpG-ODN) have been verified as an effective antineoplastic agent for intravesical application in a murine orthotopic C57-BL6 /MB-49 urothelial cell carcinoma (UCC). To date, many details in the mode of action have remained unclear. Preceding studies pointed towards a Th1-weighted response. The aim of this work was to identify the local lymphocyte subsets in murine tumour-bearing bladders and to examine effects on the expression of Intercellular Adhesion Molecule 1 (ICAM-1) after treatment with CpG-ODN. MATERIAL AND METHODS Different instillation schedules were applied in an established orthotopic C57-BL6 /MB49 UCC model. After 13 days, fresh frozen sections of the harvested bladders were immunohistochemically examined for the infiltration density of lymphocytes expressing CD 3, CD4, CD8 and CD19. In a second series of the same animal model, healthy and tumour-bearing bladders were exposed to CpG-ODN or PBS and later stained for the expression of ICAM-1. RESULTS CpG-ODN instillation led to augmented T-cell infiltration (represented by CD3). Further T-cell subdifferentiation between T-helper cells (CD4) and cytotoxic T cells (CD 8a) did not show a perceptible variety between groups. The B-cell population (CD19) was found to decrease over the course of treatment. In the second series, treatment provoked a strong expression of ICAM-1 by infiltrating leukocytes, endothelial cells and particularly by the cancer cells themselves. DISCUSSION The previously observed augmented lymphocyte density was classified as T-cell infiltration. The decline of the B-cell concentration over the course of treatment suggests a Th2 suppression in favour of a Th-1 polarisation. These findings support the assumption that a cell-mediated immune response is the mode of action underlying the antineoplastic CpG-ODN capacities. The marked upregulation of ICAM-1 expression, especially on tumour cells, suggests a crucial role of this membrane protein for the initiation and maintenance of anticancer immune response. CONCLUSION CpG-ODN might be a prospective alternative to established instillation therapies. With a view to the current BCG shortage and the well-known toxicities, an amplification of the topic therapy armamentarium could be achievable. The now described capability of ICAM-1 induction on carcinoma cells and, by association, the reversal of escape strategies to cancer immunity may also make the agent interesting as an adjuvant for modern checkpoint inhibition.
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Affiliation(s)
- Marwin Klebe
- Krankenhaus Nordwest, Klink für Urologie und Kinderurologie, Frankfurt
| | | | - Rainer Hofmann
- Universitätsklinikum Gießen und Marburg - Standort Marburg, Klinik für Urologie und Kinderurologie, Marburg
| | - Peter Josef Barth
- Universitätsklinikum Münster, Gerhard-Domagk-Institut für Pathologie, Münster
| | - Axel Hegele
- Urologisches Zentrum Mittelhessen, DRK-Krankenhaus Biedenkopf und Universitätsklinikum Gießen und Marburg, Klinik für Strahlentherapie, Standort Marburg
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9
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Galluzzi L, Vacchelli E, Eggermont A, Fridman WH, Galon J, Sautès-Fridman C, Tartour E, Zitvogel L, Kroemer G. Trial Watch: Experimental Toll-like receptor agonists for cancer therapy. Oncoimmunology 2021; 1:699-716. [PMID: 22934262 PMCID: PMC3429574 DOI: 10.4161/onci.20696] [Citation(s) in RCA: 165] [Impact Index Per Article: 41.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Toll-like receptors (TLRs) are prototypic pattern recognition receptors (PRRs) best known for their ability to activate the innate immune system in response to conserved microbial components such as lipopolysaccharide and double-stranded RNA. Accumulating evidence indicates that the function of TLRs is not restricted to the elicitation of innate immune responses against invading pathogens. TLRs have indeed been shown to participate in tissue repair and injury-induced regeneration as well as in adaptive immune responses against cancer. In particular, TLR4 signaling appears to be required for the efficient processing and cross-presentation of cell-associated tumor antigens by dendritic cells, which de facto underlie optimal therapeutic responses to some anticancer drugs. Thus, TLRs constitute prominent therapeutic targets for the activation/intensification of anticancer immune responses. In line with this notion, long-used preparations such as the Coley toxin (a mixture of killed Streptococcus pyogenes and Serratia marcescens bacteria) and the bacillus Calmette-Guérin (BCG, an attenuated strain of Mycobacterium bovis originally developed as a vaccine against tuberculosis), both of which have been associated with consistent anticancer responses, potently activate TLR2 and TLR4 signaling. Today, besides BCG, only one TLR agonist is FDA-approved for therapeutic use in cancer patients: imiquimod. In this Trial Watch, we will briefly present the role of TLRs in innate and cognate immunity and discuss the progress of clinical studies evaluating the safety and efficacy of experimental TLR agonists as immunostimulatory agents for oncological indications.
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Affiliation(s)
- Lorenzo Galluzzi
- Université Paris Descartes/Paris V; Sorbonne Paris Cité; Paris, France ; Institut Gustave Roussy; Villejuif, France
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10
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Khan AA, Manzoor KN, Sultan A, Saeed M, Rafique M, Noushad S, Talib A, Rentschler S, Deigner HP. Pulling the Brakes on Fast and Furious Multiple Drug-Resistant (MDR) Bacteria. Int J Mol Sci 2021; 22:E859. [PMID: 33467089 PMCID: PMC7830236 DOI: 10.3390/ijms22020859] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 01/11/2021] [Accepted: 01/13/2021] [Indexed: 12/11/2022] Open
Abstract
Life-threatening bacterial infections have been managed by antibiotics for years and have significantly improved the wellbeing and lifetime of humans. However, bacteria have always been one step ahead by inactivating the antimicrobial agent chemically or by producing certain enzymes. The alarming universal occurrence of multidrug-resistant (MDR) bacteria has compelled researchers to find alternative treatments for MDR infections. This is a menace where conventional chemotherapies are no longer promising, but several novel approaches could help. Our current review article discusses the novel approaches that can combat MDR bacteria: starting off with potential nanoparticles (NPs) that efficiently interact with microorganisms causing fatal changes in the morphology and structure of these cells; nanophotothermal therapy using inorganic NPs like AuNPs to destroy pathogenic bacterial cells; bacteriophage therapy against which bacteria develop less resistance; combination drugs that act on dissimilar targets in distinctive pathways; probiotics therapy by the secretion of antibacterial chemicals; blockage of quorum sensing signals stopping bacterial colonization, and vaccination against resistant bacterial strains along with virulence factors. All these techniques show us a promising future in the fight against MDR bacteria, which remains the greatest challenge in public health care.
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Affiliation(s)
- Abid Ali Khan
- Center for Precision Medicine, Hochschule Furtwangen University, Jakob-Kienzle-Str. 17, 78054 Villingen-Schwenningen, Germany;
- Department of Biosciences, COMSATS University Islamabad, Park Road, Tarlai Kalan, Islamabad 45550, Pakistan; (K.N.M.); (A.S.); (M.S.); (M.R.); (S.N.)
| | - Khanzadi Nazneen Manzoor
- Department of Biosciences, COMSATS University Islamabad, Park Road, Tarlai Kalan, Islamabad 45550, Pakistan; (K.N.M.); (A.S.); (M.S.); (M.R.); (S.N.)
| | - Aamir Sultan
- Department of Biosciences, COMSATS University Islamabad, Park Road, Tarlai Kalan, Islamabad 45550, Pakistan; (K.N.M.); (A.S.); (M.S.); (M.R.); (S.N.)
| | - Maria Saeed
- Department of Biosciences, COMSATS University Islamabad, Park Road, Tarlai Kalan, Islamabad 45550, Pakistan; (K.N.M.); (A.S.); (M.S.); (M.R.); (S.N.)
| | - Mahrukh Rafique
- Department of Biosciences, COMSATS University Islamabad, Park Road, Tarlai Kalan, Islamabad 45550, Pakistan; (K.N.M.); (A.S.); (M.S.); (M.R.); (S.N.)
| | - Sameen Noushad
- Department of Biosciences, COMSATS University Islamabad, Park Road, Tarlai Kalan, Islamabad 45550, Pakistan; (K.N.M.); (A.S.); (M.S.); (M.R.); (S.N.)
| | - Ayesha Talib
- Mechano(bio)chem Department, Max Planck Institute for Colloids and Interfaces, Am Mühlenberg 1, Golm, 14476 Potsdam, Germany;
| | - Simone Rentschler
- Center for Precision Medicine, Hochschule Furtwangen University, Jakob-Kienzle-Str. 17, 78054 Villingen-Schwenningen, Germany;
| | - Hans-Peter Deigner
- Center for Precision Medicine, Hochschule Furtwangen University, Jakob-Kienzle-Str. 17, 78054 Villingen-Schwenningen, Germany;
- Max Planck Institute of Colloids and Interfaces, Leipzig, Schillingallee 68, 18057 Rostock, Germany
- Faculty of Science, University of Tuebingen, Auf der Morgenstelle 8, 72076 Tuebingen, Germany
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11
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Bunch BL, Kodumudi KN, Scott E, Morse J, Weber AM, Berglund AE, Pilon-Thomas S, Markowitz J. Anti-tumor efficacy of plasmid encoding emm55 in a murine melanoma model. Cancer Immunol Immunother 2020; 69:2465-2476. [PMID: 32556443 PMCID: PMC7680263 DOI: 10.1007/s00262-020-02634-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Accepted: 06/04/2020] [Indexed: 12/31/2022]
Abstract
Emm55 is a bacterial gene derived from Streptococcus pyogenes (S. pyogenes) that was cloned into a plasmid DNA vaccine (pAc/emm55). In this study, we investigated the anti-tumor efficacy of pAc/emm55 in a B16 murine melanoma model. Intralesional (IL) injections of pAc/emm55 significantly delayed tumor growth compared to the pAc/Empty group. There was a significant increase in the CD8+ T cells infiltrating into the tumors after pAc/emm55 treatment compared to the control group. In addition, we observed that IL injection of pAc/emm55 increased antigen-specific T cell infiltration into tumors. Depletion of CD4+ or CD8+ T cells abrogated the anti-tumor effect of pAc/emm55. Combination treatment of IL injection of pAc/emm55 with anti-PD-1 antibody significantly delayed tumor growth compared to either monotherapy. pAc/emm55 treatment combined with PD-1 blockade enhanced anti-tumor immune response and improved systemic anti-tumor immunity. Together, these strategies may lead to improvements in the treatment of patients with melanoma.
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Affiliation(s)
- Brittany L Bunch
- Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA
| | - Krithika N Kodumudi
- Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA
| | - Ellen Scott
- Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA
| | - Jennifer Morse
- Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA
| | - Amy Mackay Weber
- Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA
| | - Anders E Berglund
- Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA
- Department of Oncologic Sciences, University of South Florida, Morsani College of Medicine, Tampa, FL, USA
| | - Shari Pilon-Thomas
- Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.
- Department of Oncologic Sciences, University of South Florida, Morsani College of Medicine, Tampa, FL, USA.
- Cutaneous Oncology Program, H. Lee Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, SRB-4, Tampa, FL, 33612, USA.
- Center for Immunization and Infection Research in Cancer (CIIRC), H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
| | - Joseph Markowitz
- Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.
- Department of Oncologic Sciences, University of South Florida, Morsani College of Medicine, Tampa, FL, USA.
- Immunology Program, H. Lee Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, SRB-3, Tampa, FL, 33606, USA.
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12
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Yu W, Zheng Y, Li H, Lin H, Chen Z, Tian Y, Chen H, Zhang P, Xu X, Shen Y. The Toll-like receptor ligand, CpG oligodeoxynucleotides, regulate proliferation and osteogenic differentiation of osteoblast. J Orthop Surg Res 2020; 15:327. [PMID: 32795334 PMCID: PMC7427903 DOI: 10.1186/s13018-020-01844-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2020] [Accepted: 07/30/2020] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND This study aimed to investigate the regulation of CpG oligodeoxynucleotides (ODNs) on proliferation and osteogenic differentiation of MC3T3 cells. METHODS The laser co-focusing and flow cytometry assay were employed to detect cell uptake of CpG ODN 2006. Twelve ODNs were sythesized, and their effects on proliferation and differentiation were detected by MTT and alkaline phosphatase (ALP) activity assay. Flow cytometry assay was used to examine the regulation of CpG ODN on cell cycle. Quantitative real-time PCR (qRT-PCR) and western blot were used to evaluate the regulation of CpG ODN on mRNA and protein expression of osteogenic differentiation genes. RESULTS The phosphorothioate CpG ODN 2006 could efficiently enter the MC3T3 cells in 1 h and locate in the cytoplasm. The MTT assay demonstrated CpG ODNs could promote MC3T3 cell proliferation and differentiation in the early stage, and gradually attenuated along with the increase of treating time, except for BW001 and FC001. qRT-PCR assay demonstrated that all the 12 CpG ODNs could promote the relative expression level of osteogenic differentiated genes, SP7 and OCN. In addition, western blot analysis suggested the CpG ODNs of BW001 and FC001 could increase the protein expression of P27Kip1 and Runx2 and decrease the protein expression of cyclin D1. CONCLUSION The selected CpGODNs may be a potential gene therapy for bone regeneration of periodontitis.
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Affiliation(s)
- Wenwen Yu
- Department of Periodontics, School and hospital of Stomatology, Jilin University, 1500 Qinghua Road, Changchun, Jilin, 130021, China
- Department of Orthodontics, Tianjin Key Laboratory of Oral and Maxillofacial Function Reconstruction; Tianjin Stomatological Hospital; Hospital of Stomatology, Nankai University, 75 Dagu North Road, Tianjin, 300041, China
| | - Yi Zheng
- Department of Periodontics, School and hospital of Stomatology, Jilin University, 1500 Qinghua Road, Changchun, Jilin, 130021, China
| | - Hongyan Li
- Department of Periodontics, School and hospital of Stomatology, Jilin University, 1500 Qinghua Road, Changchun, Jilin, 130021, China
| | - Hongbing Lin
- Department of Periodontics, School and hospital of Stomatology, Jilin University, 1500 Qinghua Road, Changchun, Jilin, 130021, China
| | - Zhen Chen
- Department of Periodontics, School and hospital of Stomatology, Jilin University, 1500 Qinghua Road, Changchun, Jilin, 130021, China
| | - Yue Tian
- Department of Periodontics, School and hospital of Stomatology, Jilin University, 1500 Qinghua Road, Changchun, Jilin, 130021, China
| | - Huishan Chen
- Department of Periodontics, School and hospital of Stomatology, Jilin University, 1500 Qinghua Road, Changchun, Jilin, 130021, China
| | - Peipei Zhang
- Department of Periodontics, School and hospital of Stomatology, Jilin University, 1500 Qinghua Road, Changchun, Jilin, 130021, China
| | - Xiaowei Xu
- Department of Periodontics, School and hospital of Stomatology, Jilin University, 1500 Qinghua Road, Changchun, Jilin, 130021, China
| | - Yuqin Shen
- Department of Periodontics, School and hospital of Stomatology, Jilin University, 1500 Qinghua Road, Changchun, Jilin, 130021, China.
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13
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Wang H, Yu W, Li H, Zheng Y, Chen Z, Lin H, Shen Y. N-Acetyl-l-Leucine-Polyethyleneimine-Mediated Delivery of CpG Oligodeoxynucleotides 2006 Inhibits RAW264.7 Cell Osteoclastogenesis. Drug Des Devel Ther 2020; 14:2657-2665. [PMID: 32764870 PMCID: PMC7368329 DOI: 10.2147/dddt.s241826] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Accepted: 06/03/2020] [Indexed: 11/23/2022] Open
Abstract
INTRODUCTION CpG oligodeoxynucleotides (CpG ODN) play important roles in resisting inflammation and bone resorption. However, the inherent instability and rapid degradation hinder their wider application. This study aimed to evaluate whether N-acetyl-L-leucine-modified polyethyleneimine (N-Ac-L-Leu-PEI) could effectively deliver CpG ODN 2006 to RAW264.7 cells and and if it can regulate osteoclastogenesis in vitro. MATERIALS AND METHODS Gel retardation assay was conducted to evaluate whether N- Ac-L-Leu-PEI and CpG ODN could form a stable complex. RAW264.7 cells were divided into four groups of control group, ODN group, phosphorothioate ODN group and N-Ac-L-Leu-PEI/ODN group. Fluorescence assay was conducted to evaluate the transfection rate of ODNs in different groups. Cell viability was determined by MTT assay. Cell apoptosis was determined by live-dead cell staining and flow cytometry assay. Relative expression levels of osteoclastic differentiation factors, including Nfatc, c-fos, receptor activator of nuclear factor κB (RANK), and matrix metalloproteinase 9 (MMP9), were determined by real-time PCR and Western blot. RESULTS N-Ac-L-Leu-PEI and CpG ODN could form a stable complex at a mass ratio of 1:1 (w:w). MTT assay showed that the cell viability of N-Ac-L-Leu-PEI was relatively high even at a mass ratio of 8 μg/mL. The transfection rate of N-Ac-L-Leu-PEI-ODN complex was higher than 90%. The cell proliferation and apoptosis was significantly enhanced in N-Ac-L-Leu-PEI- CpG ODN group when compared to those in phosphorothioate CpG ODN. The expression levels of Nfatc, c-fos, RANK, and MMP9 were significantly decreased in N-Ac-L-Leu-PEI/ODN complex group. DISCUSSION N-Ac-L-Leu-PEI could be a potential gene vehicle for the prevention of periodontitis-mediated bone resorption.
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Affiliation(s)
- Huining Wang
- Department of Periodontics, Institute of Stomatology, School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou325027, Zhejiang Province, People’s Republic of China
| | - Wenwen Yu
- Department of Orthodontics, School and Hospital of Stomatology, Jilin University, Changchun, Jilin130021, People’s Republic of China
- Department of Orthodontics, Tianjin Stomatological Hospital, Nankai University, Tianjin300041, People’s Republic of China
| | - Hongyan Li
- Department of Periodontics, School and Hospital of Stomatology, Jilin University, Changchun, Jilin130021,People’s Republic of China
| | - Yi Zheng
- Department of Periodontics, School and Hospital of Stomatology, Jilin University, Changchun, Jilin130021,People’s Republic of China
- Key Laboratory of Organ Regeneration & Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun, Jilin130061, People’s Republic of China
| | - Zhen Chen
- Department of Periodontics, School and Hospital of Stomatology, Jilin University, Changchun, Jilin130021,People’s Republic of China
| | - Hongbing Lin
- Department of Periodontics, School and Hospital of Stomatology, Jilin University, Changchun, Jilin130021,People’s Republic of China
| | - Yuqin Shen
- Department of Periodontics, School and Hospital of Stomatology, Jilin University, Changchun, Jilin130021,People’s Republic of China
- Key Laboratory of Organ Regeneration & Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun, Jilin130061, People’s Republic of China
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14
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Recombinant E rns-E2 protein vaccine formulated with MF59 and CPG-ODN promotes T cell immunity against bovine viral diarrhea virus infection. Vaccine 2020; 38:3881-3891. [PMID: 32280039 DOI: 10.1016/j.vaccine.2020.03.020] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Revised: 03/02/2020] [Accepted: 03/06/2020] [Indexed: 02/07/2023]
Abstract
To obtain an effective vaccine candidate against bovine viral diarrhea virus (BVDV) disease which causes great economical loss in cattle industries, recombinant Erns-E2 protein vaccine containing MF59 and CPG-ODN adjuvants was prepared and assessed in this study. The recombinant plasmid (pET32a-Erns-E2) was constructed and transformed into BL21 (DE3) cells to produce Erns-E2 protein. We immunized mice with the MF59-and CPG-ODN-adjuvanted recombinant Erns-E2 protein, E2 protein, or Erns protein, respectively. To evaluate immunogenicity and efficacy of a vaccine-adjuvant combination, mice were challenged with BVDV BJ175170 strain after immunization. All adjuvanted vaccines elicited detectable humoral and cellular immune responses, the BVDV-specific antibody titers as well as interleukin 4 (IL-4) levels in sera of mice immunized with the recombinant Erns-E2 protein were higher than in those of mice immunized with either the recombinant Erns or E2 protein. Besides, immunization with the Erns-E2 vaccines induced higher percentage of CD4+IFN-γ+, CD8+IFN-γ+ T cells and CD3+TNF-α+ T cells compared with the other vaccines. More protective efficacy against BVDV infection was acquired in the mice treated with the recombinant Erns-E2 protein, as shown by a reduction of viremia and slight pathological changes compared with both the control mice and the other vaccinated mice. Our findings suggest that the use of the recombinant Erns-E2 protein vaccine formulated with MF59 and CPG-ODN adjuvants enhances T cell responses and viral control, which warrants the Erns-E2 protein vaccine-adjuvant combination could be as a vaccine strategy to against BVDV.
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15
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Zheng Y, Yu W, Li H, Lin H, Chen Z, Chen H, Zhang P, Tian Y, Xu X, Shen Y. CpG oligodeoxynucleotides inhibit the proliferation and osteoclastic differentiation of RAW264.7 cells. RSC Adv 2020; 10:14885-14891. [PMID: 35497169 PMCID: PMC9052049 DOI: 10.1039/c9ra11036d] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Accepted: 03/31/2020] [Indexed: 01/21/2023] Open
Abstract
Clinical prevention and treatment of periodontitis-induced bone absorption remains a challenge. The anti-infection role of CpG oligodeoxynucleotides (CpG ODNs) is well known; however, their effect on osteoclasts is still unclear. Here, we show that some CpG ODNs can regulate osteoclastogenesis of RAW264.7 cells. The phosphorothioate CpG ODN was efficiently taken up by the cells within 1 h and distributed in the cytoplasm. BW006, YW001, YW002, and FC004 CpG ODNs significantly repressed cell proliferation by targeting several cyclin proteins to arrest the cells in the G2 phase and to further initiate cell apoptosis. Regarding differentiation, we selected six CpG ODNs (FC002, BW006, YW002, YW001, FC004, and MT01) that markedly inhibited the gene expression levels of Nfatc, c-fos, RANK, and MMP9. TRAP staining showed that only YW002, YW001, and FC004 suppressed osteoclast generation and maturation. These three CpG ODNs dramatically declined the protein levels of osteoclastogenic proteins by elevating the ratio of OPG/RANKL and also downregulating the inflammatory factors (TNF-α, IL-1β, IL-6, and IL-17) at different stages. Thus, the selected CpG ODNs may be a potential molecular therapy for the prevention and treatment of periodontitis-mediated bone resorption.
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Affiliation(s)
- Yi Zheng
- Department of Periodontics, Hospital of Stomatology, Jilin University 1500 Qinghua Road Changchun 130021 Jilin China .,Key Laboratory of Organ Regeneration & Transplantation of the Ministry of Education, The First Hospital of Jilin University Changchun 130061 Jilin China
| | - Wenwen Yu
- Department of Orthodontics, Hospital of Stomatology, Jilin University 1500 Qinghua Road Changchun 130021 China.,Department of Orthodontics, Tianjin Stomatological Hospital, Nankai University Tianjin 300041 China
| | - Hongyan Li
- Department of Periodontics, Hospital of Stomatology, Jilin University 1500 Qinghua Road Changchun 130021 Jilin China
| | - Hongbing Lin
- Department of Periodontics, Hospital of Stomatology, Jilin University 1500 Qinghua Road Changchun 130021 Jilin China .,Key Laboratory of Organ Regeneration & Transplantation of the Ministry of Education, The First Hospital of Jilin University Changchun 130061 Jilin China
| | - Zhen Chen
- Department of Periodontics, Hospital of Stomatology, Jilin University 1500 Qinghua Road Changchun 130021 Jilin China
| | - Huishan Chen
- Department of Periodontics, Hospital of Stomatology, Jilin University 1500 Qinghua Road Changchun 130021 Jilin China
| | - Peipei Zhang
- Department of Periodontics, Hospital of Stomatology, Jilin University 1500 Qinghua Road Changchun 130021 Jilin China
| | - Yue Tian
- Department of Periodontics, Hospital of Stomatology, Jilin University 1500 Qinghua Road Changchun 130021 Jilin China
| | - Xiaowei Xu
- Department of Periodontics, Hospital of Stomatology, Jilin University 1500 Qinghua Road Changchun 130021 Jilin China
| | - Yuqin Shen
- Department of Periodontics, Hospital of Stomatology, Jilin University 1500 Qinghua Road Changchun 130021 Jilin China .,Key Laboratory of Organ Regeneration & Transplantation of the Ministry of Education, The First Hospital of Jilin University Changchun 130061 Jilin China
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16
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Chauhan V, Singh MP. Immuno-informatics approach to design a multi-epitope vaccine to combat cytomegalovirus infection. Eur J Pharm Sci 2020; 147:105279. [DOI: 10.1016/j.ejps.2020.105279] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Revised: 02/18/2020] [Accepted: 02/22/2020] [Indexed: 01/26/2023]
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17
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Nehete PN, Williams LE, Chitta S, Nehete BP, Patel AG, Ramani MD, Wisniewski T, Scholtzova H. Class C CpG Oligodeoxynucleotide Immunomodulatory Response in Aged Squirrel Monkey ( Saimiri Boliviensis Boliviensis). Front Aging Neurosci 2020; 12:36. [PMID: 32194391 PMCID: PMC7063459 DOI: 10.3389/fnagi.2020.00036] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Accepted: 02/04/2020] [Indexed: 12/15/2022] Open
Abstract
One means of stimulating the mammalian innate immune system is via Toll-like receptor 9 (TLR9) being exposed to unmethylated cytosine-phosphate-guanine (CpG) DNA, also known as pathogen-associated molecular patterns (PAMPs) of microbial origin. Synthetic CpG oligodeoxynucleotides (ODNs) with defined CpG motifs possess broad immunostimulatory properties that make CpG ODNs suitable as therapeutic interventions in a variety of human disease conditions, including Alzheimer's disease (AD). Rodent models are often used to preclinically test the effectiveness of CpG ODN therapeutic agents for AD and other disorders. However, the translatability of findings in such models is limited due to the significant difference of the expression of TLR9 between primates and rodents. The squirrel monkey (SQM), a New World non-human primate (NHP), is known to be phylogenetically proximate to humans, and develops extensive age-dependent cerebral amyloid angiopathy (CAA), a key pathological feature of AD. Hence, this model is currently being used to test AD therapeutics. In the present study, we conducted the first examination of Class C CpG ODN's immunomodulatory role in elderly SQMs. We documented the effectiveness of CpG ODN to trigger an immune response in an aged cohort whose immune system is senescent. The specific immune response patterns detected here closely resembled CpG ODN-induced immunostimulatory patterns observed in prior human studies. Overall, our findings provide critical data regarding the immunomodulatory potential of CpG ODN in this NHP model, allowing for future translational studies of innate immunity stimulation via TLR9 agonists for diverse indications, including AD therapeutics.
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Affiliation(s)
- Pramod N. Nehete
- Department of Comparative Medicine, The University of Texas MD Anderson Cancer Center, Bastrop, TX, United States
- The University of Texas Graduate School of Biomedical Sciences, Houston, TX, United States
| | - Lawrence E. Williams
- Department of Comparative Medicine, The University of Texas MD Anderson Cancer Center, Bastrop, TX, United States
| | - Sriram Chitta
- Department of Comparative Medicine, The University of Texas MD Anderson Cancer Center, Bastrop, TX, United States
| | - Bharti P. Nehete
- Department of Comparative Medicine, The University of Texas MD Anderson Cancer Center, Bastrop, TX, United States
| | - Akash G. Patel
- Department of Neurology, Center for Cognitive Neurology, New York University School of Medicine, New York, NY, United States
| | - Margish D. Ramani
- Department of Pathology, New York University School of Medicine, New York, NY, United States
| | - Thomas Wisniewski
- Department of Neurology, Center for Cognitive Neurology, New York University School of Medicine, New York, NY, United States
- Department of Pathology, New York University School of Medicine, New York, NY, United States
- Department of Psychiatry, New York University School of Medicine, New York, NY, United States
| | - Henrieta Scholtzova
- Department of Comparative Medicine, The University of Texas MD Anderson Cancer Center, Bastrop, TX, United States
- Department of Neurology, Center for Cognitive Neurology, New York University School of Medicine, New York, NY, United States
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18
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Auderset F, Ballester M, Mastelic-Gavillet B, Fontannaz P, Chabaud-Riou M, Reveneau N, Garinot M, Mistretta N, Liu Y, Lambert PH, Ochs M, Siegrist CA. Reactivating Immunity Primed by Acellular Pertussis Vaccines in the Absence of Circulating Antibodies: Enhanced Bacterial Control by TLR9 Rather Than TLR4 Agonist-Including Formulation. Front Immunol 2019; 10:1520. [PMID: 31333656 PMCID: PMC6618515 DOI: 10.3389/fimmu.2019.01520] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Accepted: 06/18/2019] [Indexed: 11/24/2022] Open
Abstract
Pertussis is still observed in many countries despite of high vaccine coverage. Acellular pertussis (aP) vaccination is widely implemented in many countries as primary series in infants and as boosters in school-entry/adolescents/adults (including pregnant women in some). One novel strategy to improve the reactivation of aP-vaccine primed immunity could be to include genetically- detoxified pertussis toxin and novel adjuvants in aP vaccine boosters. Their preclinical evaluation is not straightforward, as it requires mimicking the human situation where T and B memory cells may persist longer than vaccine-induced circulating antibodies. Toward this objective, we developed a novel murine model including two consecutive adoptive transfers of the memory cells induced by priming and boosting, respectively. Using this model, we assessed the capacity of three novel aP vaccine candidates including genetically-detoxified pertussis toxin, pertactin, filamentous hemagglutinin, and fimbriae adsorbed to aluminum hydroxide, supplemented—or not—with Toll-Like-Receptor 4 or 9 agonists (TLR4A, TLR9A), to reactivate aP vaccine-induced immune memory and protection, reflected by bacterial clearance. In the conventional murine immunization model, TLR4A- and TLR9A-containing aP formulations induced similar aP-specific IgG antibody responses and protection against bacterial lung colonization as current aP vaccines, despite IL-5 down-modulation by both TLR4A and TLR9A and IL-17 up-modulation by TLR4A. In the absence of serum antibodies at time of boosting or exposure, TLR4A- and TLR9A-containing formulations both enhanced vaccine antibody recall compared to current aP formulations. Unexpectedly, however, protection was only increased by the TLR9A-containing vaccine, through both earlier bacterial control and accelerated clearance. This suggests that TLR9A-containing aP vaccines may better reactivate aP vaccine-primed pertussis memory and enhance protection than current or TLR4A-adjuvanted aP vaccines.
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Affiliation(s)
- Floriane Auderset
- World Health Organization Collaborating Center for Vaccine Immunology, Departments of Pathology-Immunology and Pediatrics, University of Geneva, Geneva, Switzerland
| | - Marie Ballester
- World Health Organization Collaborating Center for Vaccine Immunology, Departments of Pathology-Immunology and Pediatrics, University of Geneva, Geneva, Switzerland
| | - Beatris Mastelic-Gavillet
- World Health Organization Collaborating Center for Vaccine Immunology, Departments of Pathology-Immunology and Pediatrics, University of Geneva, Geneva, Switzerland
| | - Paola Fontannaz
- World Health Organization Collaborating Center for Vaccine Immunology, Departments of Pathology-Immunology and Pediatrics, University of Geneva, Geneva, Switzerland
| | | | | | | | | | | | - Paul-Henri Lambert
- World Health Organization Collaborating Center for Vaccine Immunology, Departments of Pathology-Immunology and Pediatrics, University of Geneva, Geneva, Switzerland
| | | | - Claire-Anne Siegrist
- World Health Organization Collaborating Center for Vaccine Immunology, Departments of Pathology-Immunology and Pediatrics, University of Geneva, Geneva, Switzerland
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19
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Chauhan V, Rungta T, Goyal K, Singh MP. Designing a multi-epitope based vaccine to combat Kaposi Sarcoma utilizing immunoinformatics approach. Sci Rep 2019; 9:2517. [PMID: 30792446 PMCID: PMC6385272 DOI: 10.1038/s41598-019-39299-8] [Citation(s) in RCA: 99] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Accepted: 01/22/2019] [Indexed: 01/29/2023] Open
Abstract
Kaposi's sarcoma-associated herpesvirus (KSHV) responsible for causing Kaposi sarcoma (KS), an opportunistic angioproliferative neoplasm is emerging rapidly. Despite this there is no permanent cure for this disease. The present study was aimed to design a multi-epitope based vaccine targeting the major glycoproteins of KSHV which plays an important role in the virus entry. After the application of rigorous immunoinformatics analysis and several immune filters, the multi-epitope vaccine was constructed, consisting of CD4, CD8 and IFN-γ inducing epitopes. Several physiochemical characteristics, allergenicity and antigenicity of the multi-epitope vaccine were analyzed in order to ensure its safety and immunogenicity. Further, the binding affinity and stability of the vaccine with Toll like receptor -9 (TLR-9) was analyzed by molecular docking and dynamics simulation studies. In addition, an in silico cloning was performed to ensure the expression and translation efficiency of the vaccine, utilizing pET-28a (+) vector. Such T-cell-based immunotherapies which leverage this mechanism could prove their potential against cancer. Further, the authors propose to test the present findings in the lab settings to ensure the safety, immunogenicity and efficacy of the presented vaccine which may help in controlling KSHV infection.
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MESH Headings
- Amino Acid Sequence/genetics
- Cancer Vaccines/genetics
- Cancer Vaccines/immunology
- Cell Proliferation/genetics
- Computational Biology
- Epitopes, B-Lymphocyte/genetics
- Epitopes, B-Lymphocyte/immunology
- Epitopes, T-Lymphocyte/genetics
- Epitopes, T-Lymphocyte/immunology
- Glycoproteins/genetics
- Glycoproteins/immunology
- Herpesvirus 8, Human/immunology
- Herpesvirus 8, Human/pathogenicity
- Humans
- Molecular Docking Simulation
- Sarcoma, Kaposi/genetics
- Sarcoma, Kaposi/immunology
- Sarcoma, Kaposi/prevention & control
- Sarcoma, Kaposi/virology
- Toll-Like Receptor 9/genetics
- Vaccines, Subunit/genetics
- Vaccines, Subunit/immunology
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Affiliation(s)
- Varun Chauhan
- Department of Virology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, Punjab, 160012, India
| | - Tripti Rungta
- Department of Virology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, Punjab, 160012, India
| | - Kapil Goyal
- Department of Virology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, Punjab, 160012, India
| | - Mini P Singh
- Department of Virology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, Punjab, 160012, India.
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20
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Lin LCW, Chattopadhyay S, Lin JC, Hu CMJ. Advances and Opportunities in Nanoparticle- and Nanomaterial-Based Vaccines against Bacterial Infections. Adv Healthc Mater 2018; 7:e1701395. [PMID: 29508547 DOI: 10.1002/adhm.201701395] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2017] [Revised: 01/22/2018] [Indexed: 02/06/2023]
Abstract
As the dawn of the postantibiotic era we approach, antibacterial vaccines are becoming increasingly important for managing bacterial infection and reducing the need for antibiotics. Despite the success of vaccination, vaccines remain unavailable for many pressing microbial diseases, including tuberculosis, chlamydia, and staphylococcus infections. Amid continuing research efforts in antibacterial vaccine development, the advancement of nanomaterial engineering has brought forth new opportunities in vaccine designs. With increasing knowledge in antibacterial immunity and immunologic adjuvants, innovative nanoparticles are designed to elicit the appropriate immune responses for effective antimicrobial defense. Rationally designed nanoparticles are demonstrated to overcome delivery barriers to shape the adaptive immunity. This article reviews the advances in nanoparticle- and nanomaterial-based antibacterial vaccines and summarizes the development of nanoparticulate adjuvants for immune potentiation against microbial pathogens. In addition, challenges and progress in ongoing antibacterial vaccine development are discussed to highlight the opportunities for future vaccine designs.
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Affiliation(s)
- Leon Chien-Wei Lin
- Institute of Biomedical Sciences; Academia Sinica; 128, Sec. 2, Academia Road Nangang District Taipei 11529 Taiwan
| | - Saborni Chattopadhyay
- Institute of Biomedical Sciences; Academia Sinica; 128, Sec. 2, Academia Road Nangang District Taipei 11529 Taiwan
| | - Jung-Chen Lin
- Institute of Biomedical Sciences; Academia Sinica; 128, Sec. 2, Academia Road Nangang District Taipei 11529 Taiwan
| | - Che-Ming Jack Hu
- Institute of Biomedical Sciences; Academia Sinica; 128, Sec. 2, Academia Road Nangang District Taipei 11529 Taiwan
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21
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Jiang X, Guan S, Qiao Y, Li X, Xu Y, Yang L, Kuai Z, Zhang H, Shi Y, Kong W, Shan Y, Zhang H. Effects of poly(I:C) and MF59 co-adjuvants on immunogenicity and efficacy of survivin polypeptide immunogen against melanoma. J Cell Physiol 2017; 233:4926-4934. [PMID: 29206298 DOI: 10.1002/jcp.26317] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2017] [Accepted: 12/04/2017] [Indexed: 12/22/2022]
Abstract
Malignant tumors pose a public health problem that jeopardizes human life and quality of living. At present, tumor vaccines in clinical research typically are aimed at stimulating the cellular immune response, while more effective vaccines should take into account the synergy between broad spectrum antibodies and high levels of cellular immunity. In this study, epitope peptides (68-81, 95-104, 80-88) of the tumor antigen survivin were chosen as immunogens and supplemented with poly(I:C) and/or MF59 adjuvant to evaluate the immune effects and anti-melanoma activities. The results indicated that poly(I:C) and MF59 could assist the survivin epitope peptide immunogen to control the tumor size, quality, and volume in black melanoma mouse models. Analyses by antibody titering, antibody isotyping and ELISPOT suggested that the adjuvanted immunogen could induce humoral immunity in mice. Poly(I:C) and MF59 combined with survivin peptide 95-104 could effectively induce humoral immunity mediated by type 2 T helper (Th2) cells. This study provides a basis for candidate immunogen design based on survivin and provides support for tumor therapy that can induce a more balanced Th1/Th2 immune response.
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Affiliation(s)
- Xiaoyu Jiang
- National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, Jilin, China
| | - Shanshan Guan
- National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, Jilin, China
| | - Yongbo Qiao
- National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, Jilin, China
| | - Xiao Li
- National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, Jilin, China
| | - Yan Xu
- National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, Jilin, China
| | - Lan Yang
- National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, Jilin, China
| | - Ziyu Kuai
- National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, Jilin, China
| | - Haihong Zhang
- National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, Jilin, China
| | - Yuhua Shi
- National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, Jilin, China
| | - Wei Kong
- National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, Jilin, China.,Key Laboratory for Molecular Enzymology and Engineering, The Ministry of Education, School of Life Sciences, Jilin University, Changchun, Jilin, China
| | - Yaming Shan
- National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, Jilin, China.,Key Laboratory for Molecular Enzymology and Engineering, The Ministry of Education, School of Life Sciences, Jilin University, Changchun, Jilin, China
| | - Hao Zhang
- Laboratory of Theoretical and Computational Chemistry, Institute of Theoretical Chemistry, Jilin University, Changchun, Jilin, China
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22
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Guo S, Li H, Ma M, Fu J, Dong Y, Guo P. Size, Shape, and Sequence-Dependent Immunogenicity of RNA Nanoparticles. MOLECULAR THERAPY. NUCLEIC ACIDS 2017; 9:399-408. [PMID: 29246318 PMCID: PMC5701797 DOI: 10.1016/j.omtn.2017.10.010] [Citation(s) in RCA: 81] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/09/2017] [Revised: 10/14/2017] [Accepted: 10/14/2017] [Indexed: 02/01/2023]
Abstract
RNA molecules have emerged as promising therapeutics. Like all other drugs, the safety profile and immune response are important criteria for drug evaluation. However, the literature on RNA immunogenicity has been controversial. Here, we used the approach of RNA nanotechnology to demonstrate that the immune response of RNA nanoparticles is size, shape, and sequence dependent. RNA triangle, square, pentagon, and tetrahedron with same shape but different sizes, or same size but different shapes were used as models to investigate the immune response. The levels of pro-inflammatory cytokines induced by these RNA nanoarchitectures were assessed in macrophage-like cells and animals. It was found that RNA polygons without extension at the vertexes were immune inert. However, when single-stranded RNA with a specific sequence was extended from the vertexes of RNA polygons, strong immune responses were detected. These immunostimulations are sequence specific, because some other extended sequences induced little or no immune response. Additionally, larger-size RNA square induced stronger cytokine secretion. 3D RNA tetrahedron showed stronger immunostimulation than planar RNA triangle. These results suggest that the immunogenicity of RNA nanoparticles is tunable to produce either a minimal immune response that can serve as safe therapeutic vectors, or a strong immune response for cancer immunotherapy or vaccine adjuvants.
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Affiliation(s)
- Sijin Guo
- Center for RNA Nanobiotechnology and Nanomedicine, The Ohio State University, Columbus, OH 43210, USA; College of Pharmacy, Division of Pharmaceutics and Pharmaceutical Chemistry, The Ohio State University, Columbus, OH 43210, USA
| | - Hui Li
- Center for RNA Nanobiotechnology and Nanomedicine, The Ohio State University, Columbus, OH 43210, USA; College of Pharmacy, Division of Pharmaceutics and Pharmaceutical Chemistry, The Ohio State University, Columbus, OH 43210, USA
| | - Mengshi Ma
- Center for Research on Environmental Disease, College of Medicine, Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY 40506, USA
| | - Jian Fu
- Center for Research on Environmental Disease, College of Medicine, Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY 40506, USA
| | - Yizhou Dong
- Center for RNA Nanobiotechnology and Nanomedicine, The Ohio State University, Columbus, OH 43210, USA; College of Pharmacy, Division of Pharmaceutics and Pharmaceutical Chemistry, The Ohio State University, Columbus, OH 43210, USA; Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH 43210, USA; NCI Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.
| | - Peixuan Guo
- Center for RNA Nanobiotechnology and Nanomedicine, The Ohio State University, Columbus, OH 43210, USA; College of Pharmacy, Division of Pharmaceutics and Pharmaceutical Chemistry, The Ohio State University, Columbus, OH 43210, USA; College of Medicine, The Ohio State University, Columbus, OH 43210, USA; Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH 43210, USA; NCI Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.
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23
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Reeman S, Gates AJ, Pulford DJ, Krieg A, Ulaeto DO. Protection of Mice from Lethal Vaccinia Virus Infection by Vaccinia Virus Protein Subunits with a CpG Adjuvant. Viruses 2017; 9:v9120378. [PMID: 29232844 PMCID: PMC5744152 DOI: 10.3390/v9120378] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2017] [Revised: 12/03/2017] [Accepted: 12/04/2017] [Indexed: 12/23/2022] Open
Abstract
Smallpox vaccination carries a high risk of adverse events in recipients with a variety of contra-indications for live vaccines. Although alternative non-replicating vaccines have been described in the form of replication-deficient vaccine viruses, DNA vaccines, and subunit vaccines, these are less efficacious than replicating vaccines in animal models. DNA and subunit vaccines in particular have not been shown to give equivalent protection to the traditional replicating smallpox vaccine. We show here that combinations of the orthopoxvirus A27, A33, B5 and L1 proteins give differing levels of protection when administered in different combinations with different adjuvants. In particular, the combination of B5 and A27 proteins adjuvanted with CpG oligodeoxynucleotides (ODN) gives a level of protection in mice that is equivalent to the Lister traditional vaccine in a lethal vaccinia virus challenge model.
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Affiliation(s)
- Sarah Reeman
- Chemical, Biological & Radiological Division, Dstl Porton Down, Salisbury SP4 0JQ, UK.
| | - Amanda J Gates
- Chemical, Biological & Radiological Division, Dstl Porton Down, Salisbury SP4 0JQ, UK.
| | - David J Pulford
- Animal Health Laboratory, Ministry for Primary Industries, Wallaceville, Upper Hutt 5140, New Zealand.
| | - Art Krieg
- Checkmate Pharmaceuticals, One Broadway, 14th Floor, Cambridge, MA 02142, USA.
| | - David O Ulaeto
- Chemical, Biological & Radiological Division, Dstl Porton Down, Salisbury SP4 0JQ, UK.
- The Pirbright Institute, Pirbright GU24 0NF, UK.
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24
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Ohtsuki S, Takahashi Y, Inoue T, Takakura Y, Nishikawa M. Reconstruction of Toll-like receptor 9-mediated responses in HEK-Blue hTLR9 cells by transfection of human macrophage scavenger receptor 1 gene. Sci Rep 2017; 7:13661. [PMID: 29057947 PMCID: PMC5651873 DOI: 10.1038/s41598-017-13890-3] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2017] [Accepted: 10/02/2017] [Indexed: 01/05/2023] Open
Abstract
We used human Toll-like receptor 9 (hTLR9)-expressing HEK-Blue hTLR9 cells, which release secreted embryonic alkaline phosphatase (SEAP) upon response to CpG DNA, to evaluate the immunological properties of nucleic acid drug candidates. Our preliminary studies showed that phosphodiester CpG DNA hardly induced any SEAP secretion in HEK-Blue hTLR9 cells. In the current study, therefore, we developed HEK-Blue hTLR9 cells transduced with human macrophage scavenger receptor-1 (hMSR1), a cell-surface DNA receptor, and determined whether HEK-Blue hTLR9/hMSR1 cells respond to phosphorothioate (PS) CpG DNA and phosphodiester (PO) CpG DNA. We selected PS CpG2006, a single-stranded PO CpG DNA (ssCpG), and a tetrapod-like structured DNA (tetrapodna) containing ssCpG (tetraCpG) as model TLR9 ligands. Alexa Fluor 488-labeled ligands were used for flow cytometry. Unlike the mock-transfected HEK-Blue hTLR9 cells, the HEK-Blue hTLR9/hMSR1 cells efficiently took up all three CpG DNAs. SEAP release was almost proportional to the uptake. Treatment of HEK-Blue hTLR9/hMSR1 cells with an anti-hMSR1 antibody significantly reduced the uptake of ssCpG and tetraCpG. Collectively, reconstruction of TLR9-mediated responses to CpG DNA in HEK-Blue hTLR9 cells can be used to evaluate the toxicity of nucleic acid drug candidates with diverse physicochemical properties.
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Affiliation(s)
- Shozo Ohtsuki
- Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan
| | - Yuki Takahashi
- Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan
| | - Takao Inoue
- Division of Molecular Target and Gene Therapy Products, National Institute of Health Sciences, Setagaya-ku, Tokyo, 158-8501, Japan
| | - Yoshinobu Takakura
- Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan
| | - Makiya Nishikawa
- Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan. .,Laboratory of Biopharmaceutics, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba, 278-8510, Japan.
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25
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Signorini L, Delbue S, Ferrante P, Bregni M. Review on the immunotherapy strategies against metastatic colorectal carcinoma. Immunotherapy 2017; 8:1245-61. [PMID: 27605072 DOI: 10.2217/imt-2016-0045] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most common malignancies throughout the world and the leading cause of cancer-related mortality in Western countries. Recent progress in CRC treatment options, such as surgery, chemotherapy, radiotherapy and target therapy, has improved the prognosis, but advanced disease with recurrence or distant metastasis is usually incurable and has an unfavorable prognosis. The introduction of immunotherapy-associated strategies, both active and passive, to the treatment of CRC aims to overcome the limits of classical treatments. We review the state of the art for CRC with respect to different immunotherapeutic approaches, such as the use of cancer vaccines and/or adoptive cellular therapy, their most current advances and limitations and perspectives for further improvements.
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Affiliation(s)
- Lucia Signorini
- Department of Biomedical, Surgical & Dental Sciences, Via Pascal, 36, University of Milano, 20123 Milano, Italy
| | - Serena Delbue
- Department of Biomedical, Surgical & Dental Sciences, Via Pascal, 36, University of Milano, 20123 Milano, Italy
| | - Pasquale Ferrante
- Department of Biomedical, Surgical & Dental Sciences, Via Pascal, 36, University of Milano, 20123 Milano, Italy
| | - Marco Bregni
- Ospedale di Circolo di Busto Arsizio, Via A. Da Brescia, 1, 21052 Busto Arsizio VA, Italy
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26
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Paz S, Hsiao J, Cauntay P, Soriano A, Bai L, Machemer T, Xiao X, Guo S, Hung G, Younis H, Bennett CF, Henry S, Yun TJ, Burel S. The Distinct and Cooperative Roles of Toll-Like Receptor 9 and Receptor for Advanced Glycation End Products in Modulating In Vivo Inflammatory Responses to Select CpG and Non-CpG Oligonucleotides. Nucleic Acid Ther 2017; 27:272-284. [PMID: 28605247 DOI: 10.1089/nat.2017.0668] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Antisense oligonucleotides (ASOs) are widely accepted therapeutic agents that suppress RNA transcription. While the majority of ASOs are well tolerated in vivo, few sequences trigger inflammatory responses in absence of conventional CpG motifs. In this study, we identified non-CpG oligodeoxy-nucleotide (ODN) capable of triggering an inflammatory response resulting in B cell and macrophage activation in a MyD88- and TLR9-dependent manner. In addition, we found the receptor for advance glycation end product (RAGE) receptor to be involved in the initiation of inflammatory response to suboptimal concentrations of both CpG- and non-CpG-containing ODNs. In contrast, dosing RAGE KO mice with high doses of CpG or non-CpG ODNs lead to a stronger inflammatory response than observed in wild-type mice. Together, our data provide a previously uncharacterized in vivo mechanism contingent on ODN-administered dose, where TLR9 governs the primary response and RAGE plays a distinct and cooperative function in providing a pivotal role in balancing the immune response.
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Affiliation(s)
- Suzanne Paz
- IONIS Pharmaceuticals , Carlsbad, California
| | - Jill Hsiao
- IONIS Pharmaceuticals , Carlsbad, California
| | | | | | | | | | | | - Shuling Guo
- IONIS Pharmaceuticals , Carlsbad, California
| | - Gene Hung
- IONIS Pharmaceuticals , Carlsbad, California
| | | | | | - Scott Henry
- IONIS Pharmaceuticals , Carlsbad, California
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27
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Intraperitoneal immunotherapy: historical perspectives and modern therapy. Cancer Gene Ther 2016; 23:373-381. [PMID: 27834358 DOI: 10.1038/cgt.2016.49] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Revised: 09/12/2016] [Accepted: 09/19/2016] [Indexed: 12/18/2022]
Abstract
Intraperitoneal immunotherapy represents a novel strategy for the management of peritoneal metastases (PM). Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has remained the gold standard of treatment for patients with PM, yet despite optimal treatment, recurrence rates remain high and long-term survival poor. From Coley's toxins to immune checkpoint inhibitors, the wide variety of anticancer immunotherapeutic strategies are now garnering attention for control of regional disease of the peritoneal cavity. Early studies with vaccine-based therapies, adoptive cell transfer, immune checkpoint inhibitors, and chimeric T cells with tumor-specific antigen receptors (CAR-T cells) are being performed, showing promise for control of peritoneal spread and induction of lasting anticancer immunity. In addition, catumaxomab, a trifunctional antibody, has been approved for intraperitoneal immunotherapy in Europe for the control of malignant ascites in patients with epithelial cell adhesion molecule positive cancers. We review a brief history of immunotherapy and current modalities under investigation for intraperitoneal use in the treatment of PM.
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28
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Genetics, Mucosal Inflammation and the Environment in Post-Infectious Chronic Gut Syndromes. ACTA ACUST UNITED AC 2016. [DOI: 10.1038/ajgsup.2016.14] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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29
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Malignant melanoma—The cradle of anti-neoplastic immunotherapy. Crit Rev Oncol Hematol 2016; 106:25-54. [DOI: 10.1016/j.critrevonc.2016.04.010] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2015] [Revised: 03/14/2016] [Accepted: 04/25/2016] [Indexed: 02/07/2023] Open
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30
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Abstract
The host takes use of pattern recognition receptors (PRRs) to defend against pathogen invasion or cellular damage. Among microorganism-associated molecular patterns detected by host PRRs, nucleic acids derived from bacteria or viruses are tightly supervised, providing a fundamental mechanism of host defense. Pathogenic DNAs are supposed to be detected by DNA sensors that induce the activation of NFκB or TBK1-IRF3 pathway. DNA sensor cGAS is widely expressed in innate immune cells and is a key sensor of invading DNAs in several cell types. cGAS binds to DNA, followed by a conformational change that allows the synthesis of cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) from adenosine triphosphate and guanosine triphosphate. cGAMP is a strong activator of STING that can activate IRF3 and subsequent type I interferon production. Here we describe recent progresses in DNA sensors especially cGAS in the innate immune responses against pathogenic DNAs.
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31
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Ali MF, Driscoll CB, Walters PR, Limper AH, Carmona EM. β-Glucan-Activated Human B Lymphocytes Participate in Innate Immune Responses by Releasing Proinflammatory Cytokines and Stimulating Neutrophil Chemotaxis. THE JOURNAL OF IMMUNOLOGY 2015; 195:5318-26. [PMID: 26519534 DOI: 10.4049/jimmunol.1500559] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 03/11/2015] [Accepted: 09/29/2015] [Indexed: 01/20/2023]
Abstract
B lymphocytes play an essential regulatory role in the adaptive immune response through Ab production during infection. A less known function of B lymphocytes is their ability to respond directly to infectious Ags through stimulation of pattern recognition receptors expressed on their surfaces. β-Glucans are carbohydrates present in the cell wall of many pathogenic fungi that can be detected in the peripheral blood of patients during infection. They have been shown to participate in the innate inflammatory response, as they can directly activate peripheral macrophages and dendritic cells. However, their effect as direct stimulators of B lymphocytes has not been yet fully elucidated. The aim of this study was to examine the molecular mechanisms and cytokine profiles generated following β-glucan stimulation of B lymphocytes, compared with the well-established TLR-9 agonist CpG oligodeoxynucleotide (CpG), and study the participation of β-glucan-stimulated B cells in the innate immune response. In this article, we demonstrate that β-glucan-activated B lymphocytes upregulate proinflammatory cytokines (TNF-α, IL-6, and IL-8). Of interest, β-glucan, unlike CpG, had no effect on B lymphocyte proliferation or IgM production. When compared with CpG (TLR9 agonist), β-glucan-activated cells secreted significantly higher levels of IL-8. Furthermore, IL-8 secretion was partially mediated by Dectin-1 and required SYK, MAPKs, and the transcription factors NF-κB and AP-1. Moreover, we observed that conditioned media from β-glucan-stimulated B lymphocytes elicited neutrophil chemotaxis. These studies suggest that β-glucan-activated B lymphocytes have an important and novel role in fungal innate immune responses.
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Affiliation(s)
- Mohamed F Ali
- Thoracic Diseases Research Unit, Department of Medicine, Mayo Clinic and Foundation, Rochester, MN 55905; and
| | - Christopher B Driscoll
- Thoracic Diseases Research Unit, Department of Medicine, Mayo Clinic and Foundation, Rochester, MN 55905; and
| | - Paula R Walters
- Thoracic Diseases Research Unit, Department of Medicine, Mayo Clinic and Foundation, Rochester, MN 55905; and
| | - Andrew H Limper
- Thoracic Diseases Research Unit, Department of Medicine, Mayo Clinic and Foundation, Rochester, MN 55905; and Division of Pulmonary Critical Care and Internal Medicine, Department of Medicine, Mayo Clinic and Foundation, Rochester, MN 55905
| | - Eva M Carmona
- Thoracic Diseases Research Unit, Department of Medicine, Mayo Clinic and Foundation, Rochester, MN 55905; and Division of Pulmonary Critical Care and Internal Medicine, Department of Medicine, Mayo Clinic and Foundation, Rochester, MN 55905
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32
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Fernández A, Oliver L, Alvarez R, Fernández LE, Lee KP, Mesa C. Adjuvants and myeloid-derived suppressor cells: enemies or allies in therapeutic cancer vaccination. Hum Vaccin Immunother 2015; 10:3251-60. [PMID: 25483674 DOI: 10.4161/hv.29847] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Adjuvants are a critical but largely overlooked and poorly understood component included in vaccine formulations to stimulate and modulate the desired immune responses to an antigen. However, unlike in the protective infectious disease vaccines, adjuvants for cancer vaccines also need to overcome the effect of tumor-induced suppressive immune populations circulating in tumor-bearing individuals. Myeloid-derived suppressor cells (MDSC) are considered to be one of the key immunosuppressive populations that inhibit tumor-specific T cell responses in cancer patients. This review focuses on the different signals for the activation of the immune system induced by adjuvants, and the close relationship to the mechanisms of recruitment and activation of MDSC. This work explores the possibility that a cancer vaccine adjuvant may either strengthen or weaken the effect of tumor-induced MDSC, and the crucial need to address this in present and future cancer vaccines.
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Key Words
- APC, antigen-presenting cells
- ARG1, arginase 1
- CTL, cytotoxic T lymphocytes
- DC, dendritic cells
- G-MDSC, granulocytic MDSC
- GM-CSF, granulocyte macrophage colony-stimulating factor
- MDSC
- MDSC, myeloid-derived suppressor cells
- Mo-MDSC, monocytic MDSC
- NK, natural killer
- NOS2, inducible nitric oxide synthase
- TAM, tumor-associated macrophages
- TLR ligands
- TLR, Toll-like receptors
- Treg, regulatory T cells
- adjuvants
- cancer
- cytokines
- immunotherapy
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Affiliation(s)
- Audry Fernández
- a Immunobiology Division; Center of Molecular Immunology ; Havana , Cuba
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33
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Li J, Shi JL, Wu XY, Fu F, Yu J, Yuan XY, Peng Z, Cong XY, Xu SJ, Sun WB, Cheng KH, Du YJ, Wu JQ, Wang JB, Huang BH. Improvement of the Immunogenicity of Porcine Circovirus Type 2 DNA Vaccine by Recombinant ORF2 Gene and CpG Motifs. Viral Immunol 2015; 28:290-6. [PMID: 26046831 DOI: 10.1089/vim.2014.0121] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Nowadays, adjuvant is still important for boosting immunity and improving resistance in animals. In order to boost the immunity of porcine circovirus type 2 (PCV2) DNA vaccine, CpG motifs were inserted. In this study, the dose-effect was studied, and the immunity of PCV2 DNA vaccines by recombinant open reading frame 2 (ORF2) gene and CpG motifs was evaluated. Three-week-old Changbai piglets were inoculated intramuscularly with 200 μg, 400 μg, and 800 μg DNA vaccines containing 14 and 18 CpG motifs, respectively. Average gain and rectum temperature were recorded everyday during the experiments. Blood was collected from the piglets after vaccination to detect the changes of specific antibodies, interleukin-2, and immune cells every week. Tissues were collected for histopathology and polymerase chain reaction. The results indicated that compared to those of the control piglets, all concentrations of two DNA vaccines could induce PCV2-specific antibodies. A cellular immunity test showed that PCV2-specific lymphocytes proliferated the number of TH, TC, and CD3+ positive T-cells raised in the blood of DNA vaccine immune groups. There was no distinct pathological damage and viremia occurring in pigs that were inoculated with DNA vaccines, but there was some minor pathological damage in the control group. The results demonstrated that CpG motifs as an adjuvant could boost the humoral and cellular immunity of pigs to PCV2, especially in terms of cellular immunity. Comparing two DNA vaccines that were constructed, the one containing 18 CpG motifs was more effective. This is the first report that CpG motifs as an adjuvant insert to the PCV2 DNA vaccine could boost immunity.
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Affiliation(s)
- Jun Li
- 1Division of Swine Diseases, Shandong Provincial Key Laboratory of Animal Disease Control and Breeding, Institute of Animal Science and Veterinary Medicine, Shandong Academy of Agricultural Sciences, Jinan, China
| | - Jian-Li Shi
- 1Division of Swine Diseases, Shandong Provincial Key Laboratory of Animal Disease Control and Breeding, Institute of Animal Science and Veterinary Medicine, Shandong Academy of Agricultural Sciences, Jinan, China
| | - Xiao-Yan Wu
- 1Division of Swine Diseases, Shandong Provincial Key Laboratory of Animal Disease Control and Breeding, Institute of Animal Science and Veterinary Medicine, Shandong Academy of Agricultural Sciences, Jinan, China
| | - Fang Fu
- 2Division of Swine Infectious Diseases, State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
| | - Jiang Yu
- 1Division of Swine Diseases, Shandong Provincial Key Laboratory of Animal Disease Control and Breeding, Institute of Animal Science and Veterinary Medicine, Shandong Academy of Agricultural Sciences, Jinan, China
| | - Xiao-Yuan Yuan
- 1Division of Swine Diseases, Shandong Provincial Key Laboratory of Animal Disease Control and Breeding, Institute of Animal Science and Veterinary Medicine, Shandong Academy of Agricultural Sciences, Jinan, China
| | - Zhe Peng
- 1Division of Swine Diseases, Shandong Provincial Key Laboratory of Animal Disease Control and Breeding, Institute of Animal Science and Veterinary Medicine, Shandong Academy of Agricultural Sciences, Jinan, China
| | - Xiao-Yan Cong
- 1Division of Swine Diseases, Shandong Provincial Key Laboratory of Animal Disease Control and Breeding, Institute of Animal Science and Veterinary Medicine, Shandong Academy of Agricultural Sciences, Jinan, China
| | - Shao-Jian Xu
- 1Division of Swine Diseases, Shandong Provincial Key Laboratory of Animal Disease Control and Breeding, Institute of Animal Science and Veterinary Medicine, Shandong Academy of Agricultural Sciences, Jinan, China
| | - Wen-Bo Sun
- 1Division of Swine Diseases, Shandong Provincial Key Laboratory of Animal Disease Control and Breeding, Institute of Animal Science and Veterinary Medicine, Shandong Academy of Agricultural Sciences, Jinan, China
| | - Kai-Hui Cheng
- 1Division of Swine Diseases, Shandong Provincial Key Laboratory of Animal Disease Control and Breeding, Institute of Animal Science and Veterinary Medicine, Shandong Academy of Agricultural Sciences, Jinan, China
| | - Yi-Jun Du
- 1Division of Swine Diseases, Shandong Provincial Key Laboratory of Animal Disease Control and Breeding, Institute of Animal Science and Veterinary Medicine, Shandong Academy of Agricultural Sciences, Jinan, China
| | - Jia-Qiang Wu
- 1Division of Swine Diseases, Shandong Provincial Key Laboratory of Animal Disease Control and Breeding, Institute of Animal Science and Veterinary Medicine, Shandong Academy of Agricultural Sciences, Jinan, China
| | - Jin-Bao Wang
- 1Division of Swine Diseases, Shandong Provincial Key Laboratory of Animal Disease Control and Breeding, Institute of Animal Science and Veterinary Medicine, Shandong Academy of Agricultural Sciences, Jinan, China
| | - Bao-Hua Huang
- 1Division of Swine Diseases, Shandong Provincial Key Laboratory of Animal Disease Control and Breeding, Institute of Animal Science and Veterinary Medicine, Shandong Academy of Agricultural Sciences, Jinan, China
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Gooshe M, Abdolghaffari AH, Gambuzza ME, Rezaei N. The role of Toll-like receptors in multiple sclerosis and possible targeting for therapeutic purposes. Rev Neurosci 2014; 25:713-39. [PMID: 24914714 DOI: 10.1515/revneuro-2014-0026] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2014] [Accepted: 05/08/2014] [Indexed: 02/06/2023]
Abstract
The interaction between the immune and nervous systems suggests invaluable mechanisms for several pathological conditions, especially neurodegenerative disorders. Multiple sclerosis (MS) is a potentially disabling chronic autoimmune disease, characterized by chronic inflammation and neurodegenerative pathology of the central nervous system. Toll-like receptors (TLRs) are an important family of receptors involved in host defense and in recognition of invading pathogens. The role of TLRs in the pathogenesis of autoimmune disorders such as MS is only starting to be uncovered. Recent studies suggest an ameliorative role of TLR3 and a detrimental role of other TLRs in the onset and progression of MS and experimental autoimmune encephalomyelitis, a murine model of MS. Thus, modulating TLRs can represent an innovative immunotherapeutic approach in MS therapy. This article outlines the role of these TLRs in MS, also discussing TLR-targeted agonist or antagonists that could be used in the different stages of the disease.
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Tahara Y, Yasuoka J, Sawada S, Sasaki Y, Akiyoshi K. Effective CpG DNA delivery using amphiphilic cycloamylose nanogels. Biomater Sci 2014. [PMID: 26218116 DOI: 10.1039/c4bm00293h] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Unmethylated CpG oligodeoxynucleotides induce inflammatory immune responses through cytokine production and have attracted increasing attention as an immunostimulator. However, there remains a challenging issue of the use of 'native CpG DNA'. In the present study, we prepared cationic nanometer-sized gels (nanogels) consisting of cycloamylose modified with cholesterol and diethylaminoethane to form hydrophobic cross-linking points and to add positively charged groups, respectively. The cationic nanogels and native CpG DNA formed nanometer-sized complexes. Complexes of native CpG DNA with cationic nanogels delivered native CpG DNA to macrophage-like cells and induced cytokine production. In addition, complexes of negative control oligonucleotides with cationic nanogels did not induce cytokine production, and the induction of cytokines using complexes of phosphorothioate-modified CpG with cationic nanogels was lower than that of native CpG DNA. These results suggest that the complex of native CpG DNA with cationic nanogels is a promising strategy for nucleic acid adjuvants.
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Affiliation(s)
- Y Tahara
- Department of Polymer Chemistry, Graduate School of Engineering, Kyoto University, Katsura, Nishikyo-ku, Kyoto 615-8510, Japan.
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Classical versus alternative macrophage activation: the Ying and the Yang in host defense against pulmonary fungal infections. Mucosal Immunol 2014; 7:1023-35. [PMID: 25073676 DOI: 10.1038/mi.2014.65] [Citation(s) in RCA: 128] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2014] [Accepted: 06/21/2014] [Indexed: 02/04/2023]
Abstract
Macrophages are innate immune cells that possess unique abilities to polarize toward different phenotypes. Classically activated macrophages are known to have major roles in host defense against various microbial pathogens, including fungi, while alternatively activated macrophages are instrumental in immune-regulation and wound healing. Macrophages in the lungs are often the first responders to pulmonary fungal pathogens, and the macrophage polarization state has the potential to be a deciding factor in disease progression or resolution. This review discusses the distinct macrophage polarization states and their roles during pulmonary fungal infection. We focus primarily on Cryptococcus neoformans and Pneumocystis model systems as disease resolution of these two opportunistic fungal pathogens is linked to classically or alternatively activated macrophages, respectively. Further research considering macrophage polarization states that result in anti-fungal activity has the potential to provide a novel approach for the treatment of fungal infections.
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Khisamutdinov EF, Li H, Jasinski DL, Chen J, Fu J, Guo P. Enhancing immunomodulation on innate immunity by shape transition among RNA triangle, square and pentagon nanovehicles. Nucleic Acids Res 2014; 42:9996-10004. [PMID: 25092921 PMCID: PMC4150753 DOI: 10.1093/nar/gku516] [Citation(s) in RCA: 100] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/04/2022] Open
Abstract
Modulation of immune response is important in cancer immunotherapy, vaccine adjuvant development and inflammatory or immune disease therapy. Here we report the development of new immunomodulators via control of shape transition among RNA triangle, square and pentagon. Changing one RNA strand in polygons automatically induced the stretching of the interior angle from 60° to 90° or 108°, resulting in self-assembly of elegant RNA triangles, squares and pentagons. When immunological adjuvants were incorporated, their immunomodulation effect for cytokine TNF-α and IL-6 induction was greatly enhanced in vitro and in animals up to 100-fold, while RNA polygon controls induced unnoticeable effect. The RNA nanoparticles were delivered to macrophages specifically. The degree of immunostimulation greatly depended on the size, shape and number of the payload per nanoparticles. Stronger immune response was observed when the number of adjuvants per polygon was increased, demonstrating the advantage of shape transition from triangle to pentagon.
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Affiliation(s)
- Emil F Khisamutdinov
- Department of Pharmaceutical Sciences, College of Pharmacy, Markey Cancer Center, Nanobiotechnology Center, University of Kentucky, Lexington, KY 40536, USA
| | - Hui Li
- Department of Pharmaceutical Sciences, College of Pharmacy, Markey Cancer Center, Nanobiotechnology Center, University of Kentucky, Lexington, KY 40536, USA
| | - Daniel L Jasinski
- Department of Pharmaceutical Sciences, College of Pharmacy, Markey Cancer Center, Nanobiotechnology Center, University of Kentucky, Lexington, KY 40536, USA
| | - Jiao Chen
- Center for Research on Environmental Disease, Graduate Center for Toxicology, College of Medicine, University of Kentucky, Lexington, KY 40536, USA
| | - Jian Fu
- Center for Research on Environmental Disease, Graduate Center for Toxicology, College of Medicine, University of Kentucky, Lexington, KY 40536, USA
| | - Peixuan Guo
- Department of Pharmaceutical Sciences, College of Pharmacy, Markey Cancer Center, Nanobiotechnology Center, University of Kentucky, Lexington, KY 40536, USA
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Walden P, Sterry W. New and emerging vaccination strategies for prevention and treatment of dermatological diseases. Expert Rev Vaccines 2014; 3:421-31. [PMID: 15270647 DOI: 10.1586/14760584.3.4.421] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Accelerated by the rapid advancements of our understanding of the molecular and cellular pathology of diseases and of the components and mechanisms of cellular and humoral immune responses, new vaccination strategies are being developed and explored for treatment and prevention of infectious diseases, cancer, autoimmune disorders and allergies. Many newly developed vaccination strategies are already in clinical trials, some with very promising results. Although most of these strategies are still at very early stages of their development, it is foreseeable that vaccination will evolve to play an important role in prevention, treatment and management of all the above classes of diseases.
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Affiliation(s)
- Peter Walden
- Clinical Research Group for Tumor Immunology, Department of Dermatology, Venerology and Allergy, Charite - Universitatsmedizin Berlin, Humboldt University, 10098 Berlin, Germany.
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Vacchelli E, Eggermont A, Sautès-Fridman C, Galon J, Zitvogel L, Kroemer G, Galluzzi L. Trial Watch: Toll-like receptor agonists for cancer therapy. Oncoimmunology 2013; 2:e25238. [PMID: 24083080 PMCID: PMC3782517 DOI: 10.4161/onci.25238] [Citation(s) in RCA: 120] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2013] [Accepted: 05/31/2013] [Indexed: 12/19/2022] Open
Abstract
Toll-like receptors (TLRs) have long been known for their ability to initiate innate immune responses upon exposure to conserved microbial components such as lipopolysaccharide (LPS) and double-stranded RNA. More recently, this family of pattern recognition receptors has been attributed a critical role in the elicitation of anticancer immune responses, raising interest in the development of immunochemotherapeutic regimens based on natural or synthetic TLR agonists. In spite of such an intense wave of preclinical and clinical investigation, only three TLR agonists are currently licensed by FDA for use in cancer patients: bacillus Calmette-Guérin (BCG), an attenuated strain of Mycobacterium bovis that operates as a mixed TLR2/TLR4 agonist; monophosphoryl lipid A (MPL), a derivative of Salmonella minnesota that functions as a potent agonist of TLR4; and imiquimod, a synthetic imidazoquinoline that activates TLR7. One year ago, in the August and September issues of OncoImmunology, we described the main biological features of TLRs and discussed the progress of clinical studies evaluating the safety and therapeutic potential of TLR agonists in cancer patients. Here, we summarize the latest developments in this exciting area of research, focusing on preclinical studies that have been published during the last 13 mo and clinical trials launched in the same period to investigate the antineoplastic activity of TLR agonists.
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Affiliation(s)
- Erika Vacchelli
- Institut Gustave Roussy; Villejuif, France
- Université Paris-Sud/Paris XI; Le Kremlin-Bicêtre; Paris, France
- INSERM, U848; Villejuif, France
| | | | - Catherine Sautès-Fridman
- Université Paris Descartes/Paris V; Sorbonne Paris Cité; Paris, France
- Equipe 13, Centre de Recherche des Cordeliers; Paris, France
- Pôle de Biologie, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris; Paris, France
| | - Jérôme Galon
- Université Paris Descartes/Paris V; Sorbonne Paris Cité; Paris, France
- Equipe 15, Centre de Recherche des Cordeliers; Paris, France
- INSERM, U872; Paris, France
- Université Pierre et Marie Curie/Paris VI; Paris, France
| | - Laurence Zitvogel
- Université Paris-Sud/Paris XI; Le Kremlin-Bicêtre; Paris, France
- INSERM, U1015; Villejuif, France
| | - Guido Kroemer
- INSERM, U848; Villejuif, France
- Université Paris Descartes/Paris V; Sorbonne Paris Cité; Paris, France
- Pôle de Biologie, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris; Paris, France
- Equipe 11 labelisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers; Paris, France
- Metabolomics and Cell Biology Platform; Institut Gustave Roussy; Villejuif, France
| | - Lorenzo Galluzzi
- Institut Gustave Roussy; Villejuif, France
- Université Paris Descartes/Paris V; Sorbonne Paris Cité; Paris, France
- Equipe 11 labelisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers; Paris, France
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Fűri I, Sipos F, Germann TM, Kalmár A, Tulassay Z, Molnár B, Műzes G. Epithelial toll-like receptor 9 signaling in colorectal inflammation and cancer: Clinico-pathogenic aspects. World J Gastroenterol 2013; 19:4119-4126. [PMID: 23864774 PMCID: PMC3710413 DOI: 10.3748/wjg.v19.i26.4119] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2013] [Accepted: 04/29/2013] [Indexed: 02/06/2023] Open
Abstract
Toll-like receptors (TLRs) recognize specific motifs which are frequently present in bacteria, fungi, prokaryotes and viruses. Amongst TLRs, TLR9 can be activated by such bacterial or viral DNA fragments, immunoglobulin-DNA complexes or synthetic oligonucleotides, which all contain unmethylated cytosine-guanine nucleotide sequences (CpGs). Emerging data indicate that TLR9 signaling has a role in, and may influence, colorectal carcinogenesis and colonic inflammation. CpGs are classified into three groups according to their influence on both the antigen-specific humoral- and cellular immunity, and the production of type 1 interferons and proinflammatory cytokines. TLR9 activation via CpGs may serve as a new therapeutic target for several cancerous and various inflammatory conditions. Due to its probable anti-cancer effects, the application possibilities of TLR9-signaling modulation may be extremely diverse even in colorectal tumors. In this review we aimed to summarize the current knowledge about TLR-signaling in the pathogenesis and therapy of inflammatory bowel diseases and colorectal cancer. Due to the species-specific differences in TLR9 expression, however, one must be careful in translating the animal model data into the human system, because of the differences between CpG-oligodeoxynucleotide-responsive cells. TLR9 agonist DNA-based immunomodulatory sequences could also represent a promising therapeutic alternative in systemic inflammatory conditions and chronic colonic inflammations as their side effects are not significant.
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Zonneveld-Huijssoon E, Albani S, Prakken BJ, van Wijk F. Heat shock protein bystander antigens for peptide immunotherapy in autoimmune disease. Clin Exp Immunol 2013. [PMID: 23199319 DOI: 10.1111/j.1365-2249.2012.04627.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Mucosal administration of an antigen eliciting bystander suppression at the site of inflammation results in effective antigen-specific immunotherapy for autoimmune diseases. Heat shock proteins are bystander antigens that are effective in peptide-specific immunotherapy in both experimental and human autoimmune disease. The efficacy of preventive peptide immunotherapy is increased by enhancing peptide-specific immune responses with proinflammatory agents. Combining peptide-specific immunotherapy with general suppression of inflammation may improve its therapeutic effect.
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Affiliation(s)
- E Zonneveld-Huijssoon
- Department of Pediatric Immunology, Centre for Cellular and Molecular Intervention, University Medical Centre Utrecht, Utrecht, the Netherlands
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Oxidant stress in mitochondrial DNA damage, autophagy and inflammation in atherosclerosis. Sci Rep 2013; 3:1077. [PMID: 23326634 PMCID: PMC3546319 DOI: 10.1038/srep01077] [Citation(s) in RCA: 145] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2012] [Accepted: 11/29/2012] [Indexed: 12/27/2022] Open
Abstract
Our studies in HUVECs show that ox-LDL induced autophagy and damaged mtDNA leading to TLR9 expression. LOX-1 antibody or the ROS inhibitor apocynin attenuated ox-LDL-mediated autophagy, mtDNA damage and TLR9 expression, suggesting that these events are LOX-1 and ROS-dependent phenomena. Experiments using siRNA to DNase II indicated that DNase II digests mtDNA to protect the tissue from inflammation. Next, we studied and found intense autophagy, TLR9 expression and inflammatory signals (CD45 and CD68) in the aortas of LDLR knockout mice fed high cholesterol diet. Deletion of LOX-1 (LDLR/LOX-1 double knockout mice) attenuated autophagy, TLR9 expression as well as CD45 and CD68. Damaged mtDNA signal was also very high in LDLR knockout mice aortas, and this signal was attenuated by LOX-1 deletion. Thus, it appears that oxidative stress-mediated damaged mtDNA that escapes autophagy induces a potent inflammatory response in atherosclerosis.
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Zonneveld-Huijssoon E, van Wijk F, Roord S, Delemarre E, Meerding J, de Jager W, Klein M, Raz E, Albani S, Kuis W, Boes M, Prakken BJ. TLR9 agonist CpG enhances protective nasal HSP60 peptide vaccine efficacy in experimental autoimmune arthritis. Ann Rheum Dis 2012; 71:1706-15. [PMID: 22562976 DOI: 10.1136/annrheumdis-2011-201131] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
OBJECTIVES Peptide-based immune tolerance induction is considered an attractive treatment option for autoimmune diseases. The authors have developed a novel method that can enhance the induction of protective peptide-specific T-cell responses, using a rat arthritis model. The authors focused on the Toll-like receptor 9 ligand CpG, which was shown to stimulate regulatory T-cell proliferation when added to plasmacytoid dendritic cells (pDC) using in-vitro cultures. METHODS The peptide used is a heat shock protein 60 epitope (p1) that elicits tolerogenic peptide-specific immune responses in human arthritis patients and was recently shown to have protective capacity as a bystander antigen in the rat adjuvant arthritis model. Rats were treated with three nasal doses of p1, CpG or a combination of p1 and CpG. Antigen-presenting cells were studied in nose-draining lymph nodes (mandibular lymph nodes; MLN) after nasal treatment, and T-cell responses were analysed in joint-draining lymph nodes after arthritis induction. RESULTS Nasal co-administration of p1/CpG significantly augmented the arthritis-protective effect of p1, while CpG treatment alone did not. Co-treatment of p1/CpG increased both the number and activation status of pDC in draining MLN, which was accompanied by amplified p1-specific T-cell proliferation and interleukin (IL)-10 production. During early arthritis, p1-specific IL-10 production was identified at the site of inflammation. P1 and p1/CpG-treated rats showed a greater amount of CD4+FoxP3+ regulatory T cells in the joint-draining lymph nodes, which correlated with lower arthritis scores. CONCLUSIONS These clinical and immunological data suggest the use of CpG as a potent adjuvant for mucosal peptide-specific immune therapy in arthritis.
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MESH Headings
- Adjuvants, Immunologic/administration & dosage
- Administration, Intranasal
- Animals
- Arthritis, Experimental/immunology
- Arthritis, Rheumatoid/immunology
- Chaperonin 60/administration & dosage
- Chaperonin 60/immunology
- Dendritic Cells/immunology
- Disease Models, Animal
- Epitopes, T-Lymphocyte/immunology
- Lymphocyte Activation/immunology
- Male
- Oligodeoxyribonucleotides/administration & dosage
- Oligodeoxyribonucleotides/immunology
- Rats
- Rats, Inbred Lew
- T-Lymphocytes, Regulatory/immunology
- Toll-Like Receptor 9/agonists
- Vaccines, Subunit/administration & dosage
- Vaccines, Subunit/immunology
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Affiliation(s)
- Evelien Zonneveld-Huijssoon
- Department of Pediatric Immunology, University Medical Centre Utrecht, Centre for Molecular and Cellular Intervention, Lundlaan 6, 3584 EA Utrecht, The Netherlands
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Karbach J, Neumann A, Brand K, Wahle C, Siegel E, Maeurer M, Ritter E, Tsuji T, Gnjatic S, Old LJ, Ritter G, Jäger E. Phase I clinical trial of mixed bacterial vaccine (Coley's toxins) in patients with NY-ESO-1 expressing cancers: immunological effects and clinical activity. Clin Cancer Res 2012; 18:5449-59. [PMID: 22847809 DOI: 10.1158/1078-0432.ccr-12-1116] [Citation(s) in RCA: 68] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE Mixed bacterial vaccine (MBV, Coley's toxins) is a historical, vaguely defined preparation of heat-inactivated Streptococcus pyogenes and Serratia marcescens used as nonspecific immunotherapy in the treatment of cancer. The mechanism of action is suspected to have an immunologic basis, yet it is poorly defined up to now. We developed a new, biochemically well defined and current good manufacturing practice-compliant MBV preparation, which has been investigated in patients with NY-ESO-1 expressing cancers. EXPERIMENTAL DESIGN Patients received MBV subcutaneously at a starting dose of 250 EU (endotoxin units) twice a week. The MBV dose was escalated in each patient until a body temperature of 38°C to 39.5°C was induced or up to the maximum dose of 547.000 EU. Changes in serum cytokine levels were determined and immune responses to NY-ESO-1 were evaluated. Tumor response was assessed according to RECIST. RESULTS Twelve patients were enrolled and 11 of them developed fever after the administration of MBV. Ten of 12 patients showed a consistent increase in serum IL-6 levels with the highest levels coinciding with the highest body temperature. A subgroup of patients showed increasing levels of TNF-α, IFN-γ, and IL1-β. A patient with metastatic bladder cancer showed a partial tumor response strongly correlated with MBV-induced fever and highly elevated levels of several cytokines. CONCLUSIONS MBV at fever-inducing dose levels can lead to a massive induction of immunoregulatory cytokines that may be involved in inducing tumor regressions. We propose to further explore the role of MBV as a potent immune modulator at higher dose levels and in conjunction with antigen-specific cancer vaccines.
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Affiliation(s)
- Julia Karbach
- Klinik für Onkologie und Hämatologie, Krankenhaus Nordwest, Frankfurt, Germany
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Rattanakiat S, Nishikawa M, Takakura Y. Self-assembling CpG DNA nanoparticles for efficient antigen delivery and immunostimulation. Eur J Pharm Sci 2012; 47:352-8. [PMID: 22771546 DOI: 10.1016/j.ejps.2012.06.015] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2011] [Revised: 04/25/2012] [Accepted: 06/25/2012] [Indexed: 10/28/2022]
Abstract
DNA containing unmethylated deoxycytidylyl-deoxyguanosine (CpG) dinucleotides (CpG DNA) is a potent stimulator of immune responses through triggering of Toll-like receptor 9 (TLR9). In the present study, we synthesized cholesterol-modified CpG oligodeoxynucleotide (Chol-CpG ODN) and investigated its ability to form nanoparticles by self-assembling, then examined their immunostimulatory activity and potency to deliver antigens to antigen presenting cells (APCs). Chol-CpG ODN spontaneously formed particles in aqueous solutions. Cholesterol modification increased the stability of ODN in serum. Chol-CpG ODN was efficiently taken up by mouse macrophage-like RAW264.7 cells and induced a large amount of tumor necrosis factor-α compared with unmodified CpG ODN. Then, ovalbumin (OVA), a model antigen, was incorporated into Chol-CpG ODN nanoparticles. Cholesterol-modified GpC ODN (Chol-GpC ODN) was used to assess the importance of CpG motif on the antigen-specific immune response. Vaccination of mice with OVA/Chol-CpG ODN induced high level interferon-γ production from splenocytes. Furthermore, a high serum level of OVA-specific immunoglobulin G2a was observed in mice receiving OVA/Chol-CpG ODN. Neither CpG ODN nor Chol-GpC ODN was effective at all. These results indicate that self-assembling nanoparticles of Chol-CpG ODN are effective for inducing antigen-specific immune responses because of the high immunostimulatory activity, ability to incorporate antigens and tropism to APCs.
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Affiliation(s)
- Sakulrat Rattanakiat
- Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
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Intratumoral delivery of CpG-conjugated anti-MUC1 antibody enhances NK cell anti-tumor activity. Cancer Immunol Immunother 2012; 61:2055-65. [PMID: 22543528 DOI: 10.1007/s00262-012-1264-y] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2011] [Accepted: 04/10/2012] [Indexed: 12/14/2022]
Abstract
Monoclonal antibodies (mAbs) against tumor-associated antigens are useful anticancer agents. Antibody-dependent cellular cytotoxicity (ADCC) is one of the major mechanisms responsible for initiating natural killer cell (NK)-mediated killing of tumors. However, the regulation of ADCC via NK cells is poorly understood. We have investigated the cytolytic activity of NK cells against pancreatic cancer cells that were coated with an antibody directed against the human tumor antigen, Mucin-1 designated HMFG-2, either alone or conjugated to CpG oligodeoxynucleotide (CpG ODN). Conjugated antibodies were tested for their ability to elicit ADCC in vitro and in vivo against pancreatic cancer cells. NK cells cultured in the presence of immobilized CpG ODN, HMFG-2 Ab, or CpG ODN-conjugated HMFG-2 Ab were able to up-regulate perforin similarly. Interestingly, a significant higher ADCC was observed when CpG ODN-conjugated HMFG-2-coated tumor cells were co-cultured with NK cells compared to unconjugated HMFG-2 Ab or CpG ODN alone. Moreover, MyD88-deficient NK cells can perform ADCC in vitro. Furthermore, intratumoral injections of CpG ODN-conjugated HMFG-2 induced a significant reduction in tumor burden in vivo in an established model of pancreatic tumor in nude mice compared to CpG ODN or the HMFG-2 alone. Depletion of macrophages or NK cells before treatment confirmed that both cells were required for the anti-tumor response in vivo. Results also suggest that CpG ODN and HMFG-2 Ab could be sensed by NK cells on the mAb-coated tumor cells triggering enhanced ADCC in vitro and in vivo.
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Rumio C, Sommariva M, Sfondrini L, Palazzo M, Morelli D, Viganò L, De Cecco L, Tagliabue E, Balsari A. Induction of Paneth cell degranulation by orally administered Toll-like receptor ligands. J Cell Physiol 2012; 227:1107-13. [PMID: 21567398 DOI: 10.1002/jcp.22830] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The secretory activity of Paneth cells is related to the bacterial milieu in the small intestine; however, the molecules involved in inducing Paneth cell secretion of enzymes and antimicrobial peptides are not well-defined. Mice treated orally with CpG-oligodeoxynucleotide (ODN), an agonist of Toll-like receptor (TLR) 9, showed rapid and massive Paneth cell degranulation. CpG-ODN-induced degranulation was not observed in TLR9(-/-) mice or in chimeric TLR9(-/-) mice reconstituted with wild-type (WT) bone marrow, but was observed in WT mice reconstituted with TLR9(-/-) bone marrow, indicating a role for TLR9-expressing gastrointestinal cells in CpG recognition. The TLR3 agonist polyinosinic-polycytidylic acid also induced rapid degranulation, whereas the TLR4 and TLR5 agonists LPS and flagellin, respectively, induced late degranulation mediated by TNF-α. Our evidence that TLR9 and TLR3 agonists induce Paneth cell degranulation points to the need for further studies of the mechanisms underlying Paneth cell function as an avenue toward preventing infection and treating inflammatory bowel diseases.
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Affiliation(s)
- Cristiano Rumio
- Department of Human Morphology and Biomedical Sciences Città Studi University of Milan, Milan, Italy
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Poly D,L-lactide-co-glycolic acid-liposome encapsulated ODN on innate immunity in Epinephelus bruneus against Vibrio alginolyticus. Vet Immunol Immunopathol 2012; 147:77-85. [PMID: 22551979 DOI: 10.1016/j.vetimm.2012.04.008] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2012] [Revised: 03/26/2012] [Accepted: 04/04/2012] [Indexed: 11/23/2022]
Abstract
The efficacy of poly D,L-lactide-co-glycolic acid (PLGA)-liposome (L) encapsulated oligodeoxynucleotides with unmethylated deoxycytidyl-deoxyguanosine motifs (CpG-ODNs) on innate and adaptive immune response and disease resistance in kelp grouper (Epinephelus bruneus) against Vibrio alginolyticus at weeks 1, 2, and 4 is reported. The superoxide dismutase (SOD), respiratory burst, and lysozyme activities significantly increased in E. bruneus when immunized with ODN, PLGA+ODN, L+ODN, and PLGA+L+ODN on weeks 2 and 4. The serum complement activity was significantly enhanced with L+ODN and PLGA+L+ODN on week 1 while it increased with PLGA+ODN, L+ODN, and PLGA+L+ODN on weeks 2 and 4. The antibody titre consistently was increased with PLGA or L encapsulated with ODN (PLGA+ODN, L+ODN, and PLGA+L+ODN) from weeks 1 to 4. The cumulative mortality was 20% each in PLGA+ODN administered groups and 15% each in ODN, L+ODN, and PLGA+L+ODN groups during a period of 30 days. The present study suggests that PLGA-liposome encapsulated ODN has the potential to modulate the immune system and can serve as a useful tool for further design of immunoprophylatic nano drug formulations against bacterial diseases.
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Abstract
The past decade has revealed that melanoma is comprised of multiple subclasses that can be categorized on the basis of key features, including the clinical stage of disease, the oncogenic molecular 'drivers', the anatomical location or the behaviour of the primary lesion and the expression of specific biomarkers. Although exercises in subclassification are not new in oncology, progress in this area has produced both conceptual and clinical breakthroughs, which, for melanoma, are unprecedented in the modern history of the disease. This Review focuses on these recent striking advances in the strategy of molecularly targeted approaches to the therapy of melanoma in humans.
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Affiliation(s)
- Keith T Flaherty
- Massachusetts General Hospital Cancer Center, 55 Fruit Street, Boston, Massachusetts 02114, USA
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Del-Rio-Navarro BE, Espinosa-Rosales FJ, Flenady V, Sienra-Monge JJL. Cochrane Review: Immunostimulants for preventing respiratory tract infection in children. ACTA ACUST UNITED AC 2012. [DOI: 10.1002/ebch.1833] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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