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Treatment of COVID-19 with remdesivir in the absence of humoral immunity: a case report

Buckland, Matthew S. ; Galloway, James B. ; Fhogartaigh, Caoimhe Nic ; [et al.]

Springer Science and Business Media LLC ; 2020

In: Nature Communications Vol. 11, No. 1 ( 2020-12-14)

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In: Nature Communications, Springer Science and Business Media LLC, Vol. 11, No. 1 ( 2020-12-14)

Abstract: The response to the coronavirus disease 2019 (COVID-19) pandemic has been hampered by lack of an effective severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antiviral therapy. Here we report the use of remdesivir in a patient with COVID-19 and the prototypic genetic antibody deficiency X-linked agammaglobulinaemia (XLA). Despite evidence of complement activation and a robust T cell response, the patient developed persistent SARS-CoV-2 pneumonitis, without progressing to multi-organ involvement. This unusual clinical course is consistent with a contribution of antibodies to both viral clearance and progression to severe disease. In the absence of these confounders, we take an experimental medicine approach to examine the in vivo utility of remdesivir. Over two independent courses of treatment, we observe a temporally correlated clinical and virological response, leading to clinical resolution and viral clearance, with no evidence of acquired drug resistance. We therefore provide evidence for the antiviral efficacy of remdesivir in vivo, and its potential benefit in selected patients.

Type of Medium: Online Resource

ISSN: 2041-1723

URL: Article

DOI: 10.1038/s41467-020-19761-2

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2020

detail.hit.zdb_id: 2553671-0

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T cell and antibody responses induced by a single dose of ChAdOx1 nCoV-19 (AZD1222) vaccine in a phase 1/2 clinical trial

Ewer, Katie J. ; Barrett, Jordan R. ; Belij-Rammerstorfer, Sandra ; [et al.]

Springer Science and Business Media LLC ; 2021

In: Nature Medicine Vol. 27, No. 2 ( 2021-02), p. 270-278

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In: Nature Medicine, Springer Science and Business Media LLC, Vol. 27, No. 2 ( 2021-02), p. 270-278

Type of Medium: Online Resource

ISSN: 1078-8956 , 1546-170X

URL: Article

DOI: 10.1038/s41591-020-01194-5

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2021

detail.hit.zdb_id: 1484517-9

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Author Correction: T cell and antibody responses induced by a single dose of ChAdOx1 nCoV-19 (AZD1222) vaccine in a phase 1/2 clinical trial

Ewer, Katie J. ; Barrett, Jordan R. ; Belij-Rammerstorfer, Sandra ; [et al.]

Springer Science and Business Media LLC ; 2021

In: Nature Medicine Vol. 27, No. 6 ( 2021-06), p. 1116-1116

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In: Nature Medicine, Springer Science and Business Media LLC, Vol. 27, No. 6 ( 2021-06), p. 1116-1116

Type of Medium: Online Resource

ISSN: 1078-8956 , 1546-170X

URL: Article

DOI: 10.1038/s41591-021-01363-0

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2021

detail.hit.zdb_id: 1484517-9

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Vaccine-elicited CD4 T cells induce immunopathology after chronic LCMV infection

Penaloza-MacMaster, Pablo ; Barber, Daniel L. ; Wherry, E. John ; [et al.]

American Association for the Advancement of Science (AAAS) ; 2015

In: Science Vol. 347, No. 6219 ( 2015-01-16), p. 278-282

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In: Science, American Association for the Advancement of Science (AAAS), Vol. 347, No. 6219 ( 2015-01-16), p. 278-282

Abstract: CD4 T cells promote innate and adaptive immune responses, but how vaccine-elicited CD4 T cells contribute to immune protection remains unclear. We evaluated whether induction of virus-specific CD4 T cells by vaccination would protect mice against infection with chronic lymphocytic choriomeningitis virus (LCMV). Immunization with vaccines that selectively induced CD4 T cell responses resulted in catastrophic inflammation and mortality after challenge with a persistent strain of LCMV. Immunopathology required antigen-specific CD4 T cells and was associated with a cytokine storm, generalized inflammation, and multi-organ system failure. Virus-specific CD8 T cells or antibodies abrogated the pathology. These data demonstrate that vaccine-elicited CD4 T cells in the absence of effective antiviral immune responses can trigger lethal immunopathology.

Type of Medium: Online Resource

ISSN: 0036-8075 , 1095-9203

URL: Article

DOI: 10.1126/science.aaa2148

RVK:

TA 1000

RVK:

WA 15000

Language: English

Publisher: American Association for the Advancement of Science (AAAS)

Publication Date: 2015

detail.hit.zdb_id: 128410-1

detail.hit.zdb_id: 2066996-3

detail.hit.zdb_id: 2060783-0

SSG: 11

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Identification of immune correlates of fatal outcomes in critically ill COVID-19 patients

Youngs, Jonathan ; Provine, Nicholas M. ; Lim, Nicholas ; [et al.]

Public Library of Science (PLoS) ; 2021

In: PLOS Pathogens Vol. 17, No. 9 ( 2021-9-16), p. e1009804-

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In: PLOS Pathogens, Public Library of Science (PLoS), Vol. 17, No. 9 ( 2021-9-16), p. e1009804-

Abstract: Prior studies have demonstrated that immunologic dysfunction underpins severe illness in COVID-19 patients, but have lacked an in-depth analysis of the immunologic drivers of death in the most critically ill patients. We performed immunophenotyping of viral antigen-specific and unconventional T cell responses, neutralizing antibodies, and serum proteins in critically ill patients with SARS-CoV-2 infection, using influenza infection, SARS-CoV-2-convalescent health care workers, and healthy adults as controls. We identify mucosal-associated invariant T (MAIT) cell activation as an independent and significant predictor of death in COVID-19 (HR = 5.92, 95% CI = 2.49–14.1). MAIT cell activation correlates with several other mortality-associated immunologic measures including broad activation of CD8 + T cells and non-Vδ2 γδT cells, and elevated levels of cytokines and chemokines, including GM-CSF, CXCL10, CCL2, and IL-6. MAIT cell activation is also a predictor of disease severity in influenza (ECMO/death HR = 4.43, 95% CI = 1.08–18.2). Single-cell RNA-sequencing reveals a shift from focused IFNα-driven signals in COVID-19 ICU patients who survive to broad pro-inflammatory responses in fatal COVID-19 –a feature not observed in severe influenza. We conclude that fatal COVID-19 infection is driven by uncoordinated inflammatory responses that drive a hierarchy of T cell activation, elements of which can serve as prognostic indicators and potential targets for immune intervention.

Type of Medium: Online Resource

ISSN: 1553-7374

URL: Article

DOI: 10.1371/journal.ppat.1009804

DOI: 10.1371/journal.ppat.1009804.g001

DOI: 10.1371/journal.ppat.1009804.g002

DOI: 10.1371/journal.ppat.1009804.g003

DOI: 10.1371/journal.ppat.1009804.g004

DOI: 10.1371/journal.ppat.1009804.g005

DOI: 10.1371/journal.ppat.1009804.g006

DOI: 10.1371/journal.ppat.1009804.g007

DOI: 10.1371/journal.ppat.1009804.t001

DOI: 10.1371/journal.ppat.1009804.s001

DOI: 10.1371/journal.ppat.1009804.s002

DOI: 10.1371/journal.ppat.1009804.s003

DOI: 10.1371/journal.ppat.1009804.s004

DOI: 10.1371/journal.ppat.1009804.s005

DOI: 10.1371/journal.ppat.1009804.s006

DOI: 10.1371/journal.ppat.1009804.s007

DOI: 10.1371/journal.ppat.1009804.s008

DOI: 10.1371/journal.ppat.1009804.s009

DOI: 10.1371/journal.ppat.1009804.s010

DOI: 10.1371/journal.ppat.1009804.s011

DOI: 10.1371/journal.ppat.1009804.s012

DOI: 10.1371/journal.ppat.1009804.s013

DOI: 10.1371/journal.ppat.1009804.s014

DOI: 10.1371/journal.ppat.1009804.s015

DOI: 10.1371/journal.ppat.1009804.s016

DOI: 10.1371/journal.ppat.1009804.s017

Language: English

Publisher: Public Library of Science (PLoS)

Publication Date: 2021

detail.hit.zdb_id: 2205412-1

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A conserved population of MHC II-restricted, innate-like, commensal-reactive T cells in the gut of humans and mice

Hackstein, Carl-Philipp ; Costigan, Dana ; Drexhage, Linnea ; [et al.]

Springer Science and Business Media LLC ; 2022

In: Nature Communications Vol. 13, No. 1 ( 2022-12-03)

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In: Nature Communications, Springer Science and Business Media LLC, Vol. 13, No. 1 ( 2022-12-03)

Abstract: Interactions with commensal microbes shape host immunity on multiple levels and play a pivotal role in human health and disease. Tissue-dwelling, antigen-specific T cells are poised to respond to local insults, making their phenotype important in the relationship between host and microbes. Here we show that MHC-II restricted, commensal-reactive T cells in the colon of both humans and mice acquire transcriptional and functional characteristics associated with innate-like T cells. This cell population is abundant and conserved in the human and murine colon and endowed with polyfunctional effector properties spanning classic Th1- and Th17-cytokines, cytotoxic molecules, and regulators of epithelial homeostasis. T cells with this phenotype are increased in ulcerative colitis patients, and their presence aggravates pathology in dextran sodium sulphate-treated mice, pointing towards a pathogenic role in colitis. Our findings add to the expanding spectrum of innate-like immune cells positioned at the frontline of intestinal immune surveillance, capable of acting as sentinels of microbes and the local cytokine milieu.

Type of Medium: Online Resource

ISSN: 2041-1723

URL: Article

DOI: 10.1038/s41467-022-35126-3

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2022

detail.hit.zdb_id: 2553671-0

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Immediate Dysfunction of Vaccine-Elicited CD8+ T Cells Primed in the Absence of CD4+ T Cells

Provine, Nicholas M. ; Larocca, Rafael A. ; Aid, Malika ; [et al.]

The American Association of Immunologists ; 2016

In: The Journal of Immunology Vol. 197, No. 5 ( 2016-09-01), p. 1809-1822

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In: The Journal of Immunology, The American Association of Immunologists, Vol. 197, No. 5 ( 2016-09-01), p. 1809-1822

Abstract: CD4+ T cell help is critical for optimal CD8+ T cell memory differentiation and maintenance in many experimental systems. In addition, many reports have identified reduced primary CD8+ T cell responses in the absence of CD4+ T cell help, which often coincides with reduced Ag or pathogen clearance. In this study, we demonstrate that absence of CD4+ T cells at the time of adenovirus vector immunization of mice led to immediate impairments in early CD8+ T cell functionality and differentiation. Unhelped CD8+ T cells exhibited a reduced effector phenotype, decreased ex vivo cytotoxicity, and decreased capacity to produce cytokines. This dysfunctional state was imprinted within 3 d of immunization. Unhelped CD8+ T cells expressed elevated levels of inhibitory receptors and exhibited transcriptomic exhaustion and anergy profiles by gene set enrichment analysis. Dysfunctional, impaired effector differentiation also occurred following immunization of CD4+ T cell–deficient mice with a poxvirus vector. This study demonstrates that following priming with viral vectors, CD4+ T cell help is required to promote both the expansion and acquisition of effector functions by CD8+ T cells, which is accomplished by preventing immediate dysfunction.

Type of Medium: Online Resource

ISSN: 0022-1767 , 1550-6606

URL: Article

DOI: 10.4049/jimmunol.1600591

RVK:

XA 54100

RVK:

XA 10000

Language: English

Publisher: The American Association of Immunologists

Publication Date: 2016

detail.hit.zdb_id: 1475085-5

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The HDAC inhibitor zabadinostat is a systemic regulator of adaptive immunity

Liu, Geng ; Barczak, Wojciech ; Lee, Lian Ni ; [et al.]

Springer Science and Business Media LLC ; 2023

In: Communications Biology Vol. 6, No. 1 ( 2023-01-26)

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In: Communications Biology, Springer Science and Business Media LLC, Vol. 6, No. 1 ( 2023-01-26)

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.

Type of Medium: Online Resource

ISSN: 2399-3642

URL: Article

DOI: 10.1038/s42003-023-04485-y

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2023

detail.hit.zdb_id: 2919698-X

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Development of novel replication-defective lymphocytic choriomeningitis virus vectors expressing SIV antigens

Penaloza MacMaster, Pablo ; Shields, Jennifer L. ; Alayo, Quazim A. ; [et al.]

Elsevier BV ; 2017

In: Vaccine Vol. 35, No. 1 ( 2017-01), p. 1-9

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In: Vaccine, Elsevier BV, Vol. 35, No. 1 ( 2017-01), p. 1-9

Type of Medium: Online Resource

ISSN: 0264-410X

URL: Article

DOI: 10.1016/j.vaccine.2016.11.063

Language: English

Publisher: Elsevier BV

Publication Date: 2017

detail.hit.zdb_id: 1468474-3

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Adenovirus vector vaccination reprograms pulmonary fibroblastic niches to support protective inflating memory CD8+ T cells

Cupovic, Jovana ; Ring, Sandra S. ; Onder, Lucas ; [et al.]

Springer Science and Business Media LLC ; 2021

In: Nature Immunology Vol. 22, No. 8 ( 2021-08), p. 1042-1051

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In: Nature Immunology, Springer Science and Business Media LLC, Vol. 22, No. 8 ( 2021-08), p. 1042-1051

Type of Medium: Online Resource

ISSN: 1529-2908 , 1529-2916

URL: Article

DOI: 10.1038/s41590-021-00969-3

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2021

detail.hit.zdb_id: 2026412-4

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