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Article ; Online: Editorial: Memory T Cells in Chronic Infections and Tumors.

Hofmann, Maike / Jandus, Camilla / Lee, Lian Ni / Utzschneider, Daniel T

2021 Volume 12, Page(s) 656010

MeSH term(s)	Animals ; Chronic Disease ; Communicable Diseases/etiology ; Communicable Diseases/metabolism ; Communicable Diseases/pathology ; Disease Susceptibility/immunology ; Humans ; Immunologic Memory ; Neoplasms/etiology ; Neoplasms/metabolism ; Neoplasms/pathology ; T-Lymphocytes/immunology ; T-Lymphocytes/metabolism
Language	English
Publishing date	2021-02-17
Publishing country	Switzerland
Document type	Editorial ; Introductory Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2021.656010
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Article ; Online: Inflation vs. Exhaustion of Antiviral CD8+ T-Cell Populations in Persistent Infections: Two Sides of the Same Coin?

Marchi, Emanuele / Lee, Lian Ni / Klenerman, Paul

Frontiers in immunology

2019 Volume 10, Page(s) 197

Abstract: Persistent virus infection can drive CD8+ T-cell responses which are markedly divergent in terms of frequency, phenotype, function, and distribution. On the one hand viruses such as Lymphocytic Choriomeningitis Virus (LCMV) Clone 13 can drive T-cell " ... ...

Abstract	Persistent virus infection can drive CD8+ T-cell responses which are markedly divergent in terms of frequency, phenotype, function, and distribution. On the one hand viruses such as Lymphocytic Choriomeningitis Virus (LCMV) Clone 13 can drive T-cell "exhaustion", associated with upregulation of checkpoint molecules, loss of effector functions, and diminished control of viral replication. On the other, low-level persistence of viruses such as Cytomegalovirus and Adenoviral vaccines can drive memory "inflation," associated with sustained populations of CD8+ T-cells over time, with maintained effector functions and a distinct phenotype. Underpinning these divergent memory pools are distinct transcriptional patterns-we aimed to compare these to explore the regulation of CD8+ T-cell memory against persistent viruses at the level of molecular networks and address whether dysregulation of specific modules may account for the phenotype observed. By exploring in parallel and also merging existing datasets derived from different investigators we attempted to develop a combined model of inflation vs. exhaustion and investigate the gene expression networks that are shared in these memory pools. In such comparisons, co-ordination of a critical module of genes driven by Tbx21 is markedly different between the two memory types. These exploratory data highlight both the molecular similarities as well as the differences between inflation and exhaustion and we hypothesize that co-ordinated regulation of a key genetic module may underpin the markedly different resultant functions and phenotypes
MeSH term(s)	Animals ; CD8-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/metabolism ; Gene Expression Profiling ; Gene Expression Regulation ; Gene Regulatory Networks ; Host-Pathogen Interactions/genetics ; Host-Pathogen Interactions/immunology ; Humans ; Immunologic Memory ; Lymphocyte Count ; Virus Diseases/blood ; Virus Diseases/genetics ; Virus Diseases/immunology ; Virus Diseases/virology ; Viruses/immunology
Language	English
Publishing date	2019-03-06
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2019.00197
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Article ; Online: Long non-coding RNA-derived peptides are immunogenic and drive a potent anti-tumour response.

Barczak, Wojciech / Carr, Simon M / Liu, Geng / Munro, Shonagh / Nicastri, Annalisa / Lee, Lian Ni / Hutchings, Claire / Ternette, Nicola / Klenerman, Paul / Kanapin, Alexander / Samsonova, Anastasia / La Thangue, Nicholas B

Nature communications

2023 Volume 14, Issue 1, Page(s) 1078

Abstract: Protein arginine methyltransferase (PRMT) 5 is over-expressed in a variety of cancers and the master transcription regulator E2F1 is an important methylation target. We have explored the role of PRMT5 and E2F1 in regulating the non-coding genome and ... ...

Abstract	Protein arginine methyltransferase (PRMT) 5 is over-expressed in a variety of cancers and the master transcription regulator E2F1 is an important methylation target. We have explored the role of PRMT5 and E2F1 in regulating the non-coding genome and report here a striking effect on long non-coding (lnc) RNA gene expression. Moreover, many MHC class I protein-associated peptides were derived from small open reading frames in the lncRNA genes. Pharmacological inhibition of PRMT5 or adjusting E2F1 levels qualitatively altered the repertoire of lncRNA-derived peptide antigens displayed by tumour cells. When presented to the immune system as either ex vivo-loaded dendritic cells or expressed from a viral vector, lncRNA-derived peptides drove a potent antigen-specific CD8 T lymphocyte response, which translated into a significant delay in tumour growth. Thus, lncRNA genes encode immunogenic peptides that can be deployed as a cancer vaccine.
MeSH term(s)	Humans ; RNA, Long Noncoding/genetics ; Neoplasms/genetics ; Neoplasms/therapy ; Histocompatibility Antigens Class I/genetics ; Histocompatibility Antigens Class I/metabolism ; Peptides/genetics ; CD8-Positive T-Lymphocytes ; Protein-Arginine N-Methyltransferases
Chemical Substances	RNA, Long Noncoding ; Histocompatibility Antigens Class I ; Peptides ; PRMT5 protein, human (EC 2.1.1.319) ; Protein-Arginine N-Methyltransferases (EC 2.1.1.319)
Language	English
Publishing date	2023-02-25
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-36826-0
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Article ; Online: The HDAC inhibitor zabadinostat is a systemic regulator of adaptive immunity.

Liu, Geng / Barczak, Wojciech / Lee, Lian Ni / Shrestha, Amit / Provine, Nicholas M / Albayrak, Gulsah / Zhu, Hong / Hutchings, Claire / Klenerman, Paul / La Thangue, Nicholas B

Communications biology

2023 Volume 6, Issue 1, Page(s) 102

Abstract: Protein acetylation plays a key role in regulating cellular processes and is subject to aberrant control in diverse pathologies. Although histone deacetylase (HDAC) inhibitors are approved drugs for certain cancers, it is not known whether they can be ... ...

Abstract	Protein acetylation plays a key role in regulating cellular processes and is subject to aberrant control in diverse pathologies. Although histone deacetylase (HDAC) inhibitors are approved drugs for certain cancers, it is not known whether they can be deployed in other therapeutic contexts. We have explored the clinical HDAC inhibitor, zabadinostat/CXD101, and found that it is a stand-alone regulator of the adaptive immune response. Zabadinostat treatment increased expression of MHC class I and II genes in a variety of cells, including dendritic cells (DCs) and healthy tissue. Remarkably, zabadinostat enhanced the activity of DCs, and CD4 and CD8 T lymphocytes. Using an antigenic peptide presented to the immune system by MHC class I, zabadinostat caused an increase in antigen-specific CD8 T lymphocytes. Further, mice immunised with covid19 spike protein and treated with zabadinostat exhibit enhanced covid19 neutralising antibodies and an increased level of T lymphocytes. The enhanced humoral response reflected increased activity of T follicular helper (Tfh) cells and germinal centre (GC) B cells. Our results argue strongly that zabadinostat has potential to augment diverse therapeutic agents that act through the immune system.
MeSH term(s)	Mice ; Animals ; Immunity, Humoral ; T-Lymphocytes, Helper-Inducer ; Histone Deacetylase Inhibitors/pharmacology ; COVID-19 ; Adaptive Immunity ; Antigens
Chemical Substances	Histone Deacetylase Inhibitors ; Antigens
Language	English
Publishing date	2023-01-26
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2399-3642
ISSN (online)	2399-3642
DOI	10.1038/s42003-023-04485-y
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Article: The Design and Development of a Multi-HBV Antigen Encoded in Chimpanzee Adenoviral and Modified Vaccinia Ankara Viral Vectors; A Novel Therapeutic Vaccine Strategy against HBV.

Chinnakannan, Senthil K / Cargill, Tamsin N / Donnison, Timothy A / Ansari, M Azim / Sebastian, Sarah / Lee, Lian Ni / Hutchings, Claire / Klenerman, Paul / Maini, Mala K / Evans, Tom / Barnes, Eleanor

Vaccines

2020 Volume 8, Issue 2

Abstract: Chronic hepatitis B virus (HBV) infection affects 257 million people globally. Current therapies suppress HBV but viral rebound occurs on cessation of therapy; novel therapeutic strategies are urgently required. To develop a therapeutic HBV vaccine that ... ...

Abstract	Chronic hepatitis B virus (HBV) infection affects 257 million people globally. Current therapies suppress HBV but viral rebound occurs on cessation of therapy; novel therapeutic strategies are urgently required. To develop a therapeutic HBV vaccine that can induce high magnitude T cells to all major HBV antigens, we have developed a novel HBV vaccine using chimpanzee adenovirus (ChAd) and modified vaccinia Ankara (MVA) viral vectors encoding multiple HBV antigens. ChAd vaccine alone generated very high magnitude HBV specific T cell responses to all HBV major antigens. The inclusion of a shark Invariant (SIi) chain genetic adjuvant significantly enhanced the magnitude of T-cells against HBV antigens. Compared to ChAd alone vaccination, ChAd-prime followed by MVA-boost vaccination further enhanced the magnitude and breadth of the vaccine induced T cell response. Intra-cellular cytokine staining study showed that HBV specific CD8+ and CD4+ T cells were polyfunctional, producing combinations of IFNγ, TNF-α, and IL-2. In summary, we have generated genetically adjuvanted ChAd and MVA vectored HBV vaccines with the potential to induce high-magnitude T cell responses through a prime-boost therapeutic vaccination approach. These pre-clinical studies pave the way for new studies of HBV therapeutic vaccination in humans with chronic hepatitis B infection.
Keywords	covid19
Language	English
Publishing date	2020-04-14
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2703319-3
ISSN	2076-393X
ISSN	2076-393X
DOI	10.3390/vaccines8020184
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Article: Single-cell transcriptome analysis of CD8

Highton, Andrew J / Zinser, Madeleine E / Lee, Lian Ni / Hutchings, Claire L / De Lara, Catherine / Phetsouphanh, Chansavath / Willberg, Chris B / Gordon, Claire L / Klenerman, Paul / Marchi, Emanuele

Wellcome open research

2019 Volume 4, Page(s) 78

Abstract: ... ...

Abstract	Background
Language	English
Publishing date	2019-05-09
Publishing country	England
Document type	Journal Article
ISSN	2398-502X
ISSN	2398-502X
DOI	10.12688/wellcomeopenres.15115.1
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Article ; Online: Induction and Maintenance of CX3CR1-Intermediate Peripheral Memory CD8

Gordon, Claire Louse / Lee, Lian Ni / Swadling, Leo / Hutchings, Claire / Zinser, Madeleine / Highton, Andrew John / Capone, Stefania / Folgori, Antonella / Barnes, Eleanor / Klenerman, Paul

Cell reports

2018 Volume 23, Issue 3, Page(s) 768–782

Abstract: The induction and maintenance of T cell memory is critical to the success of vaccines. A recently described subset of memory ... ...

Abstract	The induction and maintenance of T cell memory is critical to the success of vaccines. A recently described subset of memory CD8
MeSH term(s)	Adenoviridae/genetics ; Adenoviridae/immunology ; Adenoviridae/pathogenicity ; Adult ; Animals ; CD8-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/metabolism ; CX3C Chemokine Receptor 1/genetics ; CX3C Chemokine Receptor 1/metabolism ; Cytomegalovirus/immunology ; Cytomegalovirus/pathogenicity ; Genetic Vectors/genetics ; Genetic Vectors/metabolism ; Hepacivirus/immunology ; Hepacivirus/metabolism ; Humans ; Immunologic Memory ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Middle Aged ; Tumor Necrosis Factor Receptor Superfamily, Member 7/metabolism ; Vaccines, Synthetic/immunology ; Viral Nonstructural Proteins/genetics ; Viral Nonstructural Proteins/immunology ; Viral Nonstructural Proteins/metabolism ; Viral Vaccines/immunology ; Young Adult
Chemical Substances	CX3C Chemokine Receptor 1 ; Tumor Necrosis Factor Receptor Superfamily, Member 7 ; Vaccines, Synthetic ; Viral Nonstructural Proteins ; Viral Vaccines
Language	English
Publishing date	2018-04-17
Publishing country	United States
Document type	Journal Article
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2018.03.074
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Article ; Online: Multiple mechanisms contribute to impairment of type 1 interferon production during chronic lymphocytic choriomeningitis virus infection of mice.

Lee, Lian Ni / Burke, Shannon / Montoya, Maria / Borrow, Persephone

Journal of immunology (Baltimore, Md. : 1950)

2009 Volume 182, Issue 11, Page(s) 7178–7189

Abstract: Type 1 IFNs, innate cytokines with important effector and immunomodulatory properties, are rapidly induced in the acute phase of many virus infections; however, this is generally a transient response that is not sustained during virus persistence. To ... ...

Abstract	Type 1 IFNs, innate cytokines with important effector and immunomodulatory properties, are rapidly induced in the acute phase of many virus infections; however, this is generally a transient response that is not sustained during virus persistence. To gain insight into mechanisms that can contribute to down-regulation of type 1 IFN production during virus persistence, we analyzed type 1 IFN production during acute and chronic lymphocytic choriomeningitis virus (LCMV) infection. High-level type 1 IFN production was transiently up-regulated in cells including plasmacytoid and conventional dendritic cells (DCs) following LCMV infection of mice, but LCMV persistence was associated with only low-level type 1 IFN production. Nonetheless, chronically infected mice were able to up-regulate type 1 IFN production in response to TLR3, 7, and 9 ligands, albeit less efficiently than uninfected mice. Splenic DC numbers in mice chronically infected with LCMV were decreased, and the remaining cells exhibited a reduced response to TLR stimulation. LCMV-infected cell lines efficiently up-regulated type 1 IFN production following TLR ligation and infection with a DNA virus, but exhibited a defect in type 1 IFN induction following infection with Sendai, an RNA virus. This block in type 1 IFN production by infected cells, together with abnormalities in DC numbers and functions, likely contribute to the low-level type 1 IFN production in mice chronically infected with LCMV. Impairment of type 1 IFN production may both promote virus persistence and impact on host immunocompetence. Understanding the mechanisms involved may assist in development of strategies for control of virus persistence and superinfection.
MeSH term(s)	Animals ; DNA Viruses/immunology ; Dendritic Cells/immunology ; Gene Expression Regulation/immunology ; Interferon Type I/biosynthesis ; Lymphocytic Choriomeningitis/immunology ; Lymphocytic choriomeningitis virus/immunology ; Mice ; Plasma Cells/immunology ; RNA Viruses/immunology ; Spleen/cytology ; Toll-Like Receptors/immunology
Chemical Substances	Interferon Type I ; Toll-Like Receptors
Language	English
Publishing date	2009-06-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.0802526
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Article ; Online: Nasal associated lymphoid tissue (NALT) contributes little to protection against aerosol challenge with Mycobacterium tuberculosis after immunisation with a recombinant adenoviral vaccine.

Ronan, Edward O / Lee, Lian Ni / Tchilian, Elma Z / Beverley, Peter C L

Vaccine

2010 Volume 28, Issue 32, Page(s) 5179–5184

Abstract: Intra-nasal administration of a recombinant adenovirus expressing Mycobacterium tuberculosis antigen 85A (Ad85A) has been shown to provide protection against challenge with M. tuberculosis. However the role of the upper respiratory tract associated ... ...

Abstract	Intra-nasal administration of a recombinant adenovirus expressing Mycobacterium tuberculosis antigen 85A (Ad85A) has been shown to provide protection against challenge with M. tuberculosis. However the role of the upper respiratory tract associated lymphoid tissue, specifically the nasal associated lymphoid tissue (NALT), in providing protection has yet to be elucidated. Here we administered Ad85A to BALB/c mice alone or following BCG priming, using intranasal inocula targeting the whole respiratory tract or only the NALT, to show that Ad85A induces an immune response in the NALT insufficient to provide protection. Rather, Ad85A delivered through the respiratory tract must induce a deep lung immune response in order to protect against M. tuberculosis.
MeSH term(s)	Acyltransferases/immunology ; Adenoviridae/immunology ; Administration, Intranasal ; Animals ; Antigens, Bacterial/immunology ; BCG Vaccine/immunology ; CD8-Positive T-Lymphocytes/immunology ; Female ; Lung/immunology ; Lymphoid Tissue/immunology ; Mice ; Mice, Inbred BALB C ; Mycobacterium tuberculosis/immunology ; Nose/immunology ; Tuberculosis/immunology ; Tuberculosis/prevention & control ; Vaccines, Synthetic/immunology
Chemical Substances	Antigens, Bacterial ; BCG Vaccine ; Vaccines, Synthetic ; Acyltransferases (EC 2.3.-) ; antigen 85A, Mycobacterium tuberculosis (EC 2.3.1.-)
Language	English
Publishing date	2010-06-15
Publishing country	Netherlands
Document type	Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	605674-x
ISSN	1873-2518 ; 0264-410X
ISSN (online)	1873-2518
ISSN	0264-410X
DOI	10.1016/j.vaccine.2010.05.075
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Article ; Online: Immunization of mice with a recombinant adenovirus vaccine inhibits the early growth of Mycobacterium tuberculosis after infection.

Ronan, Edward O / Lee, Lian Ni / Beverley, Peter C L / Tchilian, Elma Z

PloS one

2009 Volume 4, Issue 12, Page(s) e8235

Abstract: Background: In pulmonary Mycobacterium tuberculosis (Mtb) infection, immune responses are delayed compared to other respiratory infections, so that antigen-specific cells are not detected in the lungs earlier than day 14. Even after parenteral ... ...

Abstract	Background: In pulmonary Mycobacterium tuberculosis (Mtb) infection, immune responses are delayed compared to other respiratory infections, so that antigen-specific cells are not detected in the lungs earlier than day 14. Even after parenteral immunization with Bacille Calmette Guerin (BCG) or a subunit vaccine, the immune response after Mtb challenge is only slightly accelerated and the kinetics of pulmonary Mtb growth do not differ between naïve and immunized animals up to day 14. Methods and findings: Mice were immunized intranasally with a recombinant adenovirus expressing mycobacterial antigen 85A (Ad85A), challenged by aerosol with Mtb and the kinetics of Mtb growth in the lungs measured. Intranasal immunization with Ad85A inhibits Mtb growth in the early phase of infection, up to day 8. Protection is sustained for at least 7 months and correlates with the presence of antigen-specific activated effector CD8 T cells in the lungs. Antigen 85A-specific T cells respond to antigen presenting cells from the lungs of mice immunized with Ad85A 23 weeks previously, demonstrating the persistence of antigen in the lungs. Conclusions/significance: Intranasal immunization with Ad85A can inhibit early growth of Mtb because it establishes a lung antigen depot and maintains an activated lung-resident lymphocyte population. We propose that an optimal immunization strategy for tuberculosis should aim to induce both lung and systemic immunity, targeting the early and late phases of Mtb growth.
MeSH term(s)	Adenoviridae/drug effects ; Adenoviridae/immunology ; Administration, Intranasal ; Animals ; Antigens, Bacterial/immunology ; Cytokines/biosynthesis ; Epitopes/immunology ; Female ; Immunity/drug effects ; Lung/drug effects ; Lung/immunology ; Lung/microbiology ; Mice ; Mice, Inbred BALB C ; Mycobacterium tuberculosis/drug effects ; Mycobacterium tuberculosis/growth & development ; Phenotype ; Time Factors ; Tuberculosis Vaccines/immunology ; Tuberculosis Vaccines/pharmacology ; Tuberculosis, Pulmonary/immunology ; Tuberculosis, Pulmonary/microbiology ; Tuberculosis, Pulmonary/prevention & control ; Vaccination ; Vaccines, Synthetic/administration & dosage ; Vaccines, Synthetic/immunology ; Vaccines, Synthetic/pharmacology
Chemical Substances	Antigens, Bacterial ; Cytokines ; Epitopes ; Tuberculosis Vaccines ; Vaccines, Synthetic
Language	English
Publishing date	2009-12-09
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0008235
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