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1.
Immunity ; 42(6): 1100-15, 2015 Jun 16.
Article in English | MEDLINE | ID: mdl-26084025

ABSTRACT

Tertiary lymphoid organs (TLOs) emerge during nonresolving peripheral inflammation, but their impact on disease progression remains unknown. We have found in aged Apoe(-/-) mice that artery TLOs (ATLOs) controlled highly territorialized aorta T cell responses. ATLOs promoted T cell recruitment, primed CD4(+) T cells, generated CD4(+), CD8(+), T regulatory (Treg) effector and central memory cells, converted naive CD4(+) T cells into induced Treg cells, and presented antigen by an unusual set of dendritic cells and B cells. Meanwhile, vascular smooth muscle cell lymphotoxin ß receptors (VSMC-LTßRs) protected against atherosclerosis by maintaining structure, cellularity, and size of ATLOs though VSMC-LTßRs did not affect secondary lymphoid organs: Atherosclerosis was markedly exacerbated in Apoe(-/-)Ltbr(-/-) and to a similar extent in aged Apoe(-/-)Ltbr(fl/fl)Tagln-cre mice. These data support the conclusion that the immune system employs ATLOs to organize aorta T cell homeostasis during aging and that VSMC-LTßRs participate in atherosclerosis protection via ATLOs.


Subject(s)
Aging/immunology , Atherosclerosis/immunology , Lymphotoxin beta Receptor/metabolism , Myocytes, Smooth Muscle/physiology , T-Lymphocyte Subsets/immunology , T-Lymphocytes, Regulatory/immunology , Adventitia/immunology , Aging/genetics , Animals , Aorta/pathology , Apolipoproteins E/genetics , Atherosclerosis/genetics , Cell Differentiation/genetics , Cell Movement/genetics , Cells, Cultured , Choristoma/immunology , Immunologic Memory , Lymphocyte Activation/genetics , Lymphoid Tissue/immunology , Lymphotoxin beta Receptor/genetics , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Microfilament Proteins/genetics , Muscle Proteins/genetics
2.
Clin Infect Dis ; 71(11): 2872-2879, 2020 12 31.
Article in English | MEDLINE | ID: mdl-31784751

ABSTRACT

BACKGROUND: In October 2015, 65 people came into direct contact with a healthcare worker presenting with a late reactivation of Ebola virus disease (EVD) in the United Kingdom. Vaccination was offered to 45 individuals with an initial assessment of high exposure risk. METHODS: Approval for rapid expanded access to the recombinant vesicular stomatitis virus-Zaire Ebola virus (rVSV-ZEBOV) vaccine as an unlicensed emergency medicine was obtained from the relevant authorities. An observational follow-up study was carried out for 1 year following vaccination. RESULTS: Twenty-six of 45 individuals elected to receive vaccination between 10 and 11 October 2015 following written informed consent. By day 14, 39% had seroconverted, increasing to 87% by day 28 and 100% by 3 months, although these responses were not always sustained. Neutralizing antibody responses were detectable in 36% by day 14 and 73% at 12 months. Common side effects included fatigue, myalgia, headache, arthralgia, and fever. These were positively associated with glycoprotein-specific T-cell but not immunoglobulin (Ig) M or IgG antibody responses. No severe vaccine-related adverse events were reported. No one exposed to the virus became infected. CONCLUSIONS: This paper reports the use of the rVSV-ZEBOV vaccine given as an emergency intervention to individuals exposed to a patient presenting with a late reactivation of EVD. The vaccine was relatively well tolerated, but a high percentage developed a fever ≥37.5°C, necessitating urgent screening for Ebola virus, and a small number developed persistent arthralgia.


Subject(s)
Ebola Vaccines/therapeutic use , Hemorrhagic Fever, Ebola , Post-Exposure Prophylaxis , Antibodies, Viral , Ebolavirus , Follow-Up Studies , Hemorrhagic Fever, Ebola/prevention & control , Humans , Recurrence , United Kingdom
3.
Circulation ; 130(16): 1363-73, 2014 Oct 14.
Article in English | MEDLINE | ID: mdl-25223984

ABSTRACT

BACKGROUND: Plasmacytoid dendritic cells (pDCs) bridge innate and adaptive immune responses and are important regulators of immuno-inflammatory diseases. However, their role in atherosclerosis remains elusive. METHODS AND RESULTS: Here, we used genetic approaches to investigate the role of pDCs in atherosclerosis. Selective pDC deficiency in vivo was achieved using CD11c-Cre × Tcf4(-/flox) bone marrow transplanted into Ldlr(-/-) mice. Compared with control Ldlr(-/-) chimeric mice, CD11c-Cre × Tcf4(-/flox) mice had reduced atherosclerosis levels. To begin to understand the mechanisms by which pDCs regulate atherosclerosis, we studied chimeric Ldlr(-/-) mice with selective MHCII deficiency on pDCs. Significantly, these mice also developed reduced atherosclerosis compared with controls without reductions in pDC numbers or changes in conventional DCs. MHCII-deficient pDCs showed defective stimulation of apolipoprotein B100-specific CD4(+) T cells in response to native low-density lipoprotein, whereas production of interferon-α was not affected. Finally, the atheroprotective effect of selective MHCII deficiency in pDCs was associated with significant reductions of proatherogenic T cell-derived interferon-γ and lesional T cell infiltration, and was abrogated in CD4(+) T cell-depleted animals. CONCLUSIONS: This study supports a proatherogenic role for pDCs in murine atherosclerosis and identifies a critical role for MHCII-restricted antigen presentation by pDCs in driving proatherogenic T cell immunity.


Subject(s)
Antigen-Presenting Cells/immunology , Atherosclerosis/immunology , Atherosclerosis/pathology , CD4-Positive T-Lymphocytes/immunology , Dendritic Cells/immunology , Histocompatibility Antigens Class II/immunology , Adaptive Immunity/immunology , Animals , Aorta/cytology , B-Lymphocytes/cytology , B-Lymphocytes/immunology , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/genetics , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/immunology , CD4-Positive T-Lymphocytes/cytology , Cell Communication/immunology , Cells, Cultured , Dendritic Cells/cytology , Flow Cytometry , Mice, Inbred C57BL , Mice, Knockout , Receptors, LDL/genetics , Receptors, LDL/immunology , Transcription Factor 4
4.
Arterioscler Thromb Vasc Biol ; 32(11): 2569-79, 2012 Nov.
Article in English | MEDLINE | ID: mdl-22936340

ABSTRACT

OBJECTIVE: Clinical studies have identified that reduced numbers of circulating plasmacytoid dendritic cells (pDCs) act as a predictor of cardiovascular events in coronary artery disease and that pDCs are detectable in the shoulder region of human atherosclerotic plaques, where rupture is most likely to occur. Results from animal models are controversial, with pDCs seen to inhibit or promote lesion development depending on the experimental settings. Here, we investigated the role of pDCs in atherosclerosis in apolipoprotein E-deficient mice. METHODS AND RESULTS: We demonstrated that the aorta and spleen of both apolipoprotein E-deficient and C57BL/6 mice displayed similar numbers of pDCs, with similar activation status. In contrast, assessment of antigen uptake/presentation using the Eα/Y-Ae system revealed that aortic pDCs in apolipoprotein E-deficient(-) mice were capable of presenting in vivo systemically administered antigen. Continuous treatment of apolipoprotein E-deficient mice with anti-mouse plasmacytoid dendritic cell antigen 1 (mPDCA-1) antibody caused specific depletion of pDCs in the aorta and spleen and significantly reduced atherosclerosis formation in the aortic sinus (by 46%; P<0.001). Depletion of pDCs also reduced macrophages (by 34%; P<0.05) and increased collagen content (by 41%; P<0.05) in aortic plaques, implying a more stable plaque phenotype. Additionally, pDC depletion reduced splenic T-cell activation and inhibited interleukin-12, chemokine (C-X-C motif) ligand 1, monokine induced by interferon-γ, interferon γ-induced protein 10, and vascular endothelium growth factor serum levels. CONCLUSIONS: These results identify a critical role for pDCs in atherosclerosis and suggest a potential role for pDC targeting in the control of the pathology.


Subject(s)
Aorta/metabolism , Aortic Diseases/etiology , Apolipoproteins E/deficiency , Atherosclerosis/etiology , Dendritic Cells/metabolism , Animals , Antibodies/administration & dosage , Antigen Presentation , Antigens, Surface/immunology , Aorta/immunology , Aorta/pathology , Aortic Diseases/genetics , Aortic Diseases/immunology , Aortic Diseases/metabolism , Aortic Diseases/pathology , Aortic Diseases/prevention & control , Apolipoproteins E/genetics , Atherosclerosis/genetics , Atherosclerosis/immunology , Atherosclerosis/metabolism , Atherosclerosis/pathology , Atherosclerosis/prevention & control , Cell Proliferation , Cells, Cultured , Dendritic Cells/immunology , Diet, High-Fat , Disease Models, Animal , Female , Genes, T-Cell Receptor alpha , Genes, T-Cell Receptor beta , Inflammation Mediators/metabolism , Injections, Intraperitoneal , Lymphocyte Activation , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Phenotype , Spleen/immunology , Spleen/metabolism , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Time Factors
5.
Nat Commun ; 12(1): 6994, 2021 11 30.
Article in English | MEDLINE | ID: mdl-34848705

ABSTRACT

The early diagnosis of active hepatitis C virus (HCV) infection remains a significant barrier to the treatment of the disease and to preventing the associated significant morbidity and mortality seen, worldwide. Current testing is delayed due to the high cost, long turnaround times and high expertise needed in centralised diagnostic laboratories. Here we demonstrate a user-friendly, low-cost pan-genotypic assay, based upon reverse transcriptase loop mediated isothermal amplification (RT-LAMP). We developed a prototype device for point-of-care use, comprising a LAMP amplification chamber and lateral flow nucleic acid detection strips, giving a visually-read, user-friendly result in <40 min. The developed assay fulfils the current guidelines recommended by World Health Organisation and is manufactured at minimal cost using simple, portable equipment. Further development of the diagnostic test will facilitate linkage between disease diagnosis and treatment, greatly improving patient care pathways and reducing loss to follow-up, so assisting in the global elimination strategy.


Subject(s)
Hepatitis C/diagnosis , Microfluidics/methods , Molecular Diagnostic Techniques/methods , Nucleic Acid Amplification Techniques/methods , Biomedical Engineering/methods , Blood Urea Nitrogen , Diagnostic Tests, Routine , Early Diagnosis , Genotype , Hepacivirus , Humans , Laboratories , Point-of-Care Systems , Viral Load , World Health Organization
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