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Article ; Online: Targeting EBV-positive B- and T/NK-cell lymphomas.

Long, Heather M

2018 Volume 132, Issue 22, Page(s) 2315–2316

MeSH term(s)	B-Lymphocytes ; Bone Marrow Transplantation ; Herpesvirus 4, Human ; Humans ; Lymphoma, Extranodal NK-T-Cell ; T-Lymphocytes
Language	English
Publishing date	2018-11-29
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood-2018-10-878587
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Article ; Online: The T-cell Response to Epstein-Barr Virus-New Tricks From an Old Dog.

Long, Heather M / Meckiff, Benjamin J / Taylor, Graham S

Frontiers in immunology

2019 Volume 10, Page(s) 2193

Abstract: Epstein-Barr virus (EBV) infects most people and establishes life-long infection controlled by the host's immune system. The genetic stability of the virus, deep understanding of the viral antigens and immune epitopes recognized by the host's T-cell ... ...

Abstract	Epstein-Barr virus (EBV) infects most people and establishes life-long infection controlled by the host's immune system. The genetic stability of the virus, deep understanding of the viral antigens and immune epitopes recognized by the host's T-cell system and the fact that recent infection can be identified by the development of symptomatic infectious mononucleosis makes EBV a powerful system in which to study human immunology. The association between EBV and multiple cancers also means that the lessons learned have strong translational potential. Increasing evidence of a role for resident memory T-cells and non-conventional γδ T-cells in controlling EBV infection suggests new opportunities for research and means the virus will continue to provide exciting new insights into human biology and immunology into the future.
MeSH term(s)	Antigens, Viral/immunology ; B-Lymphocytes/immunology ; B-Lymphocytes/pathology ; Epstein-Barr Virus Infections/immunology ; Epstein-Barr Virus Infections/pathology ; Herpesvirus 4, Human/immunology ; Humans ; Immunologic Memory ; Receptors, Antigen, T-Cell, gamma-delta/immunology ; T-Lymphocytes/immunology ; T-Lymphocytes/pathology
Chemical Substances	Antigens, Viral ; Receptors, Antigen, T-Cell, gamma-delta
Language	English
Publishing date	2019-09-18
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2019.02193
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Bioengineered small extracellular vesicles deliver multiple SARS-CoV-2 antigenic fragments and drive a broad immunological response.

Jackson, Hannah K / Long, Heather M / Yam-Puc, Juan Carlos / Palmulli, Roberta / Haigh, Tracey A / Gerber, Pehuén Pereyra / Lee, Jin S / Matheson, Nicholas J / Young, Lesley / Trowsdale, John / Lo, Mathew / Taylor, Graham S / Thaventhiran, James E / Edgar, James R

Journal of extracellular vesicles

2024 Volume 13, Issue 2, Page(s) e12412

Abstract: The COVID-19 pandemic highlighted the clear risk that zoonotic viruses pose to global health and economies. The scientific community responded by developing several efficacious vaccines which were expedited by the global need for vaccines. The emergence ... ...

Abstract	The COVID-19 pandemic highlighted the clear risk that zoonotic viruses pose to global health and economies. The scientific community responded by developing several efficacious vaccines which were expedited by the global need for vaccines. The emergence of SARS-CoV-2 breakthrough infections highlights the need for additional vaccine modalities to provide stronger, long-lived protective immunity. Here we report the design and preclinical testing of small extracellular vesicles (sEVs) as a multi-subunit vaccine. Cell lines were engineered to produce sEVs containing either the SARS-CoV-2 Spike receptor-binding domain, or an antigenic region from SARS-CoV-2 Nucleocapsid, or both in combination, and we tested their ability to evoke immune responses in vitro and in vivo. B cells incubated with bioengineered sEVs were potent activators of antigen-specific T cell clones. Mice immunised with sEVs containing both sRBD and Nucleocapsid antigens generated sRBD-specific IgGs, nucleocapsid-specific IgGs, which neutralised SARS-CoV-2 infection. sEV-based vaccines allow multiple antigens to be delivered simultaneously resulting in potent, broad immunity, and provide a quick, cheap, and reliable method to test vaccine candidates.
MeSH term(s)	Animals ; Humans ; Mice ; SARS-CoV-2 ; Pandemics ; COVID-19 ; Extracellular Vesicles ; Vaccines
Chemical Substances	Vaccines
Language	English
Publishing date	2024-02-10
Publishing country	United States
Document type	Journal Article
ZDB-ID	2683797-3
ISSN	2001-3078 ; 2001-3078
ISSN (online)	2001-3078
ISSN	2001-3078
DOI	10.1002/jev2.12412
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Article ; Online: Immunology of THymectomy And childhood CArdiac transplant (ITHACA): protocol for a UK-wide prospective observational cohort study to identify immunological risk factors of post-transplant lymphoproliferative disease (PTLD) in thymectomised children.

Offor, Ugonna T / Hollis, Paolo / Ognjanovic, Milos / Parry, Gareth / Khushnood, Abbas / Long, Heather M / Gennery, Andrew R / Bacon, Chris M / Simmonds, Jacob / Reinhardt, Zdenka / Bomken, Simon

BMJ open

2023 Volume 13, Issue 10, Page(s) e079582

Abstract: Introduction: Paediatric heart transplant patients are disproportionately affected by Epstein-Barr virus (EBV)-related post-transplant lymphoproliferative disease (PTLD) compared with other childhood solid organ recipients. The drivers for this ... ...

Abstract	Introduction: Paediatric heart transplant patients are disproportionately affected by Epstein-Barr virus (EBV)-related post-transplant lymphoproliferative disease (PTLD) compared with other childhood solid organ recipients. The drivers for this disparity remain poorly understood. A potential risk factor within this cohort is the routine surgical removal of the thymus-a gland critical for the normal development of T-lymphocyte-mediated antiviral immunity-in early life, which does not occur in other solid organ transplant recipients. Our study aims to describe the key immunological differences associated with early thymectomy, its impact on the temporal immune response to EBV infection and subsequent risk of PTLD. Methods and analysis: Prospective and sequential immune monitoring will be performed for 34 heart transplant recipients and 6 renal transplant patients (aged 0-18 years), stratified into early (<1 year), late (>1 year) and non-thymectomy groups. Peripheral blood samples and clinical data will be taken before transplant and at 3, 6, 12 and 24 months post-transplant. Single cell analysis of circulating immune cells and enumeration of EBV-specific T-lymphocytes will be performed using high-dimensional spectral flow cytometry with peptide-Major Histocompatibilty Complex (pMHC) I/II tetramer assay, respectively. The functional status of EBV-specific T-lymphocytes, along with EBV antibodies and viral load will be monitored at each of the predefined study time points. Ethics and dissemination: Ethical approval for this study has been obtained from the North of Scotland Research Ethics Committee. The results will be disseminated through publications in peer-reviewed journals, presentations at scientific conferences and patient-centred forums, including social media. Trial registration number: ISRCTN10096625.
MeSH term(s)	Child ; Humans ; Epstein-Barr Virus Infections ; Herpesvirus 4, Human/physiology ; Thymectomy/adverse effects ; Prospective Studies ; Lymphoproliferative Disorders/etiology ; Heart Transplantation/adverse effects ; Risk Factors ; Immunologic Factors ; United Kingdom ; Viral Load ; Observational Studies as Topic
Chemical Substances	Immunologic Factors
Language	English
Publishing date	2023-10-21
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2599832-8
ISSN	2044-6055 ; 2044-6055
ISSN (online)	2044-6055
ISSN	2044-6055
DOI	10.1136/bmjopen-2023-079582
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Structural definition of HLA class II-presented SARS-CoV-2 epitopes reveals a mechanism to escape pre-existing CD4

Chen, Yuan / Mason, Georgina H / Scourfield, D Oliver / Greenshields-Watson, Alexander / Haigh, Tracey A / Sewell, Andrew K / Long, Heather M / Gallimore, Awen M / Rizkallah, Pierre / MacLachlan, Bruce J / Godkin, Andrew

Cell reports

2023 Volume 42, Issue 8, Page(s) 112827

Abstract: ... ...

Abstract	CD4
MeSH term(s)	Humans ; SARS-CoV-2 ; COVID-19 ; HLA-DR1 Antigen ; Epitopes, T-Lymphocyte ; Peptides ; CD4-Positive T-Lymphocytes ; CD8-Positive T-Lymphocytes
Chemical Substances	HLA-DR1 Antigen ; Epitopes, T-Lymphocyte ; Peptides
Language	English
Publishing date	2023-07-19
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2023.112827
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Article ; Online: Cytotoxic CD4+ T-cells specific for EBV capsid antigen BORF1 are maintained in long-term latently infected healthy donors.

Dowell, Alexander C / Haigh, Tracey A / Ryan, Gordon B / Turner, James E / Long, Heather M / Taylor, Graham S

PLoS pathogens

2021 Volume 17, Issue 12, Page(s) e1010137

Abstract: Epstein Barr Virus (EBV) infects more than 95% of the population whereupon it establishes a latent infection of B-cells that persists for life under immune control. Primary EBV infection can cause infectious mononucleosis (IM) and long-term viral ... ...

Abstract	Epstein Barr Virus (EBV) infects more than 95% of the population whereupon it establishes a latent infection of B-cells that persists for life under immune control. Primary EBV infection can cause infectious mononucleosis (IM) and long-term viral carriage is associated with several malignancies and certain autoimmune diseases. Current efforts developing EBV prophylactic vaccination have focussed on neutralising antibodies. An alternative strategy, that could enhance the efficacy of such vaccines or be used alone, is to generate T-cell responses capable of recognising and eliminating newly EBV-infected cells before the virus initiates its growth transformation program. T-cell responses against the EBV structural proteins, brought into the newly infected cell by the incoming virion, are prime candidates for such responses. Here we show the structural EBV capsid proteins BcLF1, BDLF1 and BORF1 are frequent targets of T-cell responses in EBV infected people, identify new CD8+ and CD4+ T-cell epitopes and map their HLA restricting alleles. Using T-cell clones we demonstrate that CD4+ but not CD8+ T-cell clones specific for the capsid proteins can recognise newly EBV-infected B-cells and control B-cell outgrowth via cytotoxicity. Using MHC-II tetramers we show a CD4+ T-cell response to an epitope within the BORF1 capsid protein epitope is present during acute EBV infection and in long-term viral carriage. In common with other EBV-specific CD4+ T-cell responses the BORF1-specific CD4+ T-cells in IM patients expressed perforin and granzyme-B. Unexpectedly, perforin and granzyme-B expression was sustained over time even when the donor had entered the long-term infected state. These data further our understanding of EBV structural proteins as targets of T-cell responses and how CD4+ T-cell responses to EBV change from acute disease into convalescence. They also identify new targets for prophylactic EBV vaccine development.
MeSH term(s)	CD4-Positive T-Lymphocytes/immunology ; DNA-Binding Proteins/immunology ; Epstein-Barr Virus Infections/immunology ; Herpesvirus 4, Human/immunology ; Humans ; Latent Infection/immunology ; T-Lymphocytes, Cytotoxic/immunology ; Viral Proteins/immunology ; Virus Latency/immunology
Chemical Substances	BORF1 protein, Epstein-Barr virus ; DNA-Binding Proteins ; Viral Proteins
Language	English
Publishing date	2021-12-09
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7374
ISSN (online)	1553-7374
ISSN	1553-7374
DOI	10.1371/journal.ppat.1010137
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Tspan6 stimulates the chemoattractive potential of breast cancer cells for B cells in an EV- and LXR-dependent manner.

Molostvov, Guerman / Gachechiladze, Mariam / Shaaban, Abeer M / Hayward, Steven / Dean, Isaac / Dias, Irundika H K / Badr, Nahla / Danial, Irini / Mohammed, Fiyaz / Novitskaya, Vera / Paniushkina, Liliia / Speirs, Valerie / Hanby, Andrew / Nazarenko, Irina / Withers, David R / van Laere, Steven / Long, Heather M / Berditchevski, Fedor

Cell reports

2023 Volume 42, Issue 3, Page(s) 112207

Abstract: The immune microenvironment in breast cancer (BCa) is controlled by a complex network of communication between various cell types. Here, we find that recruitment of B lymphocytes to BCa tissues is controlled via mechanisms associated with cancer cell- ... ...

Abstract	The immune microenvironment in breast cancer (BCa) is controlled by a complex network of communication between various cell types. Here, we find that recruitment of B lymphocytes to BCa tissues is controlled via mechanisms associated with cancer cell-derived extracellular vesicles (CCD-EVs). Gene expression profiling identifies the Liver X receptor (LXR)-dependent transcriptional network as a key pathway that controls both CCD-EVs-induced migration of B cells and accumulation of B cells in BCa tissues. The increased accumulation oxysterol ligands for LXR (i.e., 25-hydroxycholesterol and 27-hydroxycholesterol) in CCD-EVs is regulated by the tetraspanin 6 (Tspan6). Tspan6 stimulates the chemoattractive potential of BCa cells for B cells in an EV- and LXR-dependent manner. These results demonstrate that tetraspanins control intercellular trafficking of oxysterols via CCD-EVs. Furthermore, tetraspanin-dependent changes in the oxysterol composition of CCD-EVs and the LXR signaling axis play a key role in specific changes in the tumor immune microenvironment.
MeSH term(s)	Humans ; Female ; Liver X Receptors/metabolism ; Breast Neoplasms/genetics ; Oxysterols/pharmacology ; Tetraspanins ; B-Lymphocytes/metabolism ; Tumor Microenvironment
Chemical Substances	Liver X Receptors ; Oxysterols ; Tetraspanins ; TSPAN6 protein, human
Language	English
Publishing date	2023-03-03
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2023.112207
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Article ; Online: Mutations in SARS-CoV-2 spike protein impair epitope-specific CD4

Tye, Emily X C / Jinks, Elizabeth / Haigh, Tracey A / Kaul, Baksho / Patel, Prashant / Parry, Helen M / Newby, Maddy L / Crispin, Max / Kaur, Nayandeep / Moss, Paul / Drennan, Samantha J / Taylor, Graham S / Long, Heather M

Nature immunology

2022

Abstract: ... ...

Abstract	CD4
Language	English
Publishing date	2022-12-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	2016987-5
ISSN	1529-2916 ; 1529-2908
ISSN (online)	1529-2916
ISSN	1529-2908
DOI	10.1038/s41590-022-01351-7
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Article ; Online: Complete remission of immunochemotherapy-refractory monomorphic post-transplant lymphoproliferative disorder mediated by endogenous T-cell recovery.

Bishton, Mark J / Long, Heather M / Dowell, Alexander C / Meckiff, Benjamin J / Byrne, Catherine / Fox, Christopher P

Leukemia & lymphoma

2019 Volume 60, Issue 8, Page(s) 2075–2078

MeSH term(s)	Antineoplastic Combined Chemotherapy Protocols/adverse effects ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Biopsy ; Combined Modality Therapy ; Drug Resistance, Neoplasm ; Female ; Hematopoietic Stem Cell Transplantation ; Humans ; Immune Reconstitution ; Lymphoproliferative Disorders/diagnosis ; Lymphoproliferative Disorders/etiology ; Lymphoproliferative Disorders/therapy ; Middle Aged ; Remission Induction ; Retreatment ; T-Lymphocytes/immunology ; T-Lymphocytes/metabolism ; Treatment Outcome
Language	English
Publishing date	2019-02-05
Publishing country	United States
Document type	Case Reports ; Letter ; Research Support, Non-U.S. Gov't
ZDB-ID	1042374-6
ISSN	1029-2403 ; 1042-8194
ISSN (online)	1029-2403
ISSN	1042-8194
DOI	10.1080/10428194.2019.1571203
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Article ; Online: BCL-XL inhibition by BH3-mimetic drugs induces apoptosis in models of Epstein-Barr virus-associated T/NK-cell lymphoma.

Sejic, Nenad / George, Lindsay C / Tierney, Rosemary J / Chang, Catherine / Kondrashova, Olga / MacKinnon, Ruth N / Lan, Ping / Bell, Andrew I / Lessene, Guillaume / Long, Heather M / Strasser, Andreas / Shannon-Lowe, Claire / Kelly, Gemma L

Blood advances

2020 Volume 4, Issue 19, Page(s) 4775–4787

Abstract: Epstein-Barr virus (EBV)-associated T- and natural killer (NK)-cell malignancies, such as extranodal NK-/T-cell lymphoma (ENKTL), exhibit high chemoresistance and, accordingly, such patients have a poor prognosis. The rare nature of such cancers and ... ...

Abstract	Epstein-Barr virus (EBV)-associated T- and natural killer (NK)-cell malignancies, such as extranodal NK-/T-cell lymphoma (ENKTL), exhibit high chemoresistance and, accordingly, such patients have a poor prognosis. The rare nature of such cancers and nonmalignant T/NK lymphoproliferative disorders, such as chronic active EBV (CAEBV), has limited our understanding of the pathogenesis of these diseases. Here, we characterize a panel of ENKTL- and CAEBV-derived cell lines that had been established from human tumors to be used as preclinical models of these diseases. These cell lines were interleukin-2 dependent and found to carry EBV in a latency II gene-expression pattern. All cell lines demonstrated resistance to cell death induction by DNA damage-inducing agents, the current standard of care for patients with these malignancies. This resistance was not correlated with the function of the multidrug efflux pump, P-glycoprotein. However, apoptotic cell death could be consistently induced following treatment with A-1331852, a BH3-mimetic drug that specifically inhibits the prosurvival protein BCL-XL. A-1331852-induced apoptosis was most efficacious when prosurvival MCL-1 was additionally targeted, either by BH3-mimetics or genetic deletion. Xenograft models established from the ENKTL cell line SNK6 provided evidence that A-1331852 treatment could be therapeutically beneficial in vivo. The data here suggest that therapeutic targeting of BCL-XL would be effective for patients with EBV-driven T/NK proliferative diseases, however, MCL-1 could be a potential resistance factor.
MeSH term(s)	Apoptosis ; Epstein-Barr Virus Infections/drug therapy ; Herpesvirus 4, Human ; Humans ; Killer Cells, Natural ; Pharmaceutical Preparations
Chemical Substances	Pharmaceutical Preparations
Language	English
Publishing date	2020-09-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2915908-8
ISSN	2473-9537 ; 2473-9529
ISSN (online)	2473-9537
ISSN	2473-9529
DOI	10.1182/bloodadvances.2020002446
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