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1.
HIV Med ; 22(4): 314-320, 2021 04.
Article in English | MEDLINE | ID: mdl-33295150

ABSTRACT

OBJECTIVES: Cardiovascular risk is increased in people living with HIV (PLWH). In HIV-uninfected populations, total absolute monocyte count (AMC) has been shown to be predictive of future cardiovascular events (CVEs). We sought to determine whether AMC predicts CVEs in PLWH independent of established and HIV-related cardiovascular risk factors. METHODS: We identified all PLWH within the Partners HIV Cohort without factors that could confound the monocyte count. CVE was defined as fatal or non-fatal acute myocardial infarction or ischaemic stroke. Baseline-measured AMC was defined as the average of all outpatient AMC counts a year before and after the baseline date. Multivariable Cox proportional hazards models were used to assess the association of baseline AMC with CVEs. RESULTS: Our cohort consisted of 1980 patients, with median follow-up of 10.9 years and 182 CVEs. Mean (± SD) age was 41.9 ± 9.3 years; 73.0% were male. Mean CD4 count was 506.3 ± 307.1 cells/µL, 48% had HIV viral load (VL) < 400 copies/mL, and 87% were on antiretroviral therapy. Mean AMC was 0.38 × 103  ± 0.13 cells/µL. In multivariable modelling adjusted for traditional CV risk factors, CD4 cell count, and HIV VL, AMC quartile 2 (Q2) (HR = 1.01, P = 0.98), Q3 (HR = 1.07, P = 0.76), and Q4 (HR = 0.97, P = 0.89) were not significantly predictive of CVE compared with Q1. DISCUSSION: Baseline AMC was not associated with long-term CVEs in PLWH. AMC obtained in routine clinical encounters does not appear to enhance CV risk stratification in PLWH.


Subject(s)
Brain Ischemia , HIV Infections , Stroke , Adult , HIV Infections/complications , HIV Infections/drug therapy , Humans , Male , Middle Aged , Monocytes , Retrospective Studies
2.
Hamostaseologie ; 35(1): 34-6, 2015.
Article in English | MEDLINE | ID: mdl-25375277

ABSTRACT

Shortly after myocardial infarction, various circulating leukocyte subsets accumulate in the heart. Leukocyte recruitment is highly coordinated and relies on cell production in the bone marrow, mobilization to the blood, and chemokine-mediated infiltration to the destination tissue. Neutrophils, which are phagocytic and inflammatory, are among the first leukocytes to accumulate in large numbers. Within a day, neutrophils disappear and are replaced by a subset of monocytes that further contribute to inflammation and phagocytosis. After a few days, monocyte-derived reparative macrophages accrue, quell inflammation, and foster angiogenesis and tissue remodelling. Studies suggest a well-balanced response comprising these three waves is essential to optimal infarct healing.


Subject(s)
Macrophages/immunology , Monocytes/immunology , Myocardial Ischemia/immunology , Myocarditis/immunology , Neutrophils/immunology , Regeneration/immunology , Animals , Hemostasis/immunology , Humans , Models, Cardiovascular , Models, Immunological , Myocardial Ischemia/pathology , Myocarditis/pathology , Neutrophil Activation/immunology
3.
Clin Exp Immunol ; 138(2): 213-20, 2004 Nov.
Article in English | MEDLINE | ID: mdl-15498029

ABSTRACT

Originally defined by their patterns of cytokine production, Th1 and Th2 cells have been described more recently to express other genes differentially as well, at least in vitro. In this study we compared the expression of Th1- and Th2-associated genes directly during in vivo sensitization to ovalbumin (OVA) in Th1- and Th2-polarized models of airways inflammation. Th1-polarized airway inflammation was achieved by the intranasal instillation of adenoviral vectors (Ad) encoding granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-12, followed by daily aerosolizations of OVA; instillation of Ad/GM-CSF alone with OVA aerosolization led to Th2-polarized responses. Lymph nodes were obtained at various time-points, RNA extracted, and analysed by real-time quantitative polymerase chain reaction (PCR). Consistent with reports from in vitro and human studies, mice undergoing Th1-polarized inflammation showed preferential expression of the transcription factor t-bet, the chemokines IFN-gamma inducible protein (IP)-10 and macrophage inflammatory protein 1 alpha (MIP-1-alpha), and the chemokine receptor CCR5. In contrast, the transcription factor GATA-3, the chemokines I-309 and thymus and activation regulated chemokine (TARC), and the chemokine receptors CCR3 and CCR4 were preferentially expressed in the Th2 model. Importantly, we also show that Ad/transgene expression remains compartmentalized to the lung after intranasal instillation. Flow cytometric analysis of lung myeloid dendritic cells indicated that B7.1 was expressed more strongly in the Th1 model than in the Th2 model. These studies provide a direct comparison of gene expression in in vivo Th1- and Th2-polarized models, and demonstrate that molecular events in the lymph nodes can be altered fundamentally by cytokine expression at distant mucosal sites.


Subject(s)
Cytokines/analysis , Lung/immunology , Lymph Nodes/immunology , Th1 Cells/immunology , Th2 Cells/immunology , Animals , Chemokines/analysis , Chemokines/immunology , Cytokines/immunology , DNA-Binding Proteins/analysis , Dendritic Cells/immunology , Female , Flow Cytometry/methods , GATA3 Transcription Factor , Gene Expression/immunology , Mice , Mice, Inbred BALB C , Ovalbumin/immunology , Polymerase Chain Reaction/methods , Receptors, Chemokine/analysis , Receptors, Chemokine/immunology , Respiratory Hypersensitivity/immunology , Respiratory Mucosa/immunology , T-Box Domain Proteins , Thorax/immunology , Trans-Activators/analysis , Transcription Factors/analysis , Transgenes/genetics , Transgenes/immunology
4.
Clin Exp Allergy ; 32(3): 411-21, 2002 Mar.
Article in English | MEDLINE | ID: mdl-11940072

ABSTRACT

BACKGROUND: Exposure to aerosolized harmless antigen such as ovalbumin (OVA) has previously been shown to induce inhalation tolerance, a state characterized by inhibition of IgE synthesis and airway inflammation, upon secondary immunogenic antigen encounter. Immune events associated with this phenomenon are still poorly understood. OBJECTIVE: The aim of this study was to investigate cellular and molecular mechanisms underlying this state of 'unresponsiveness'. METHODS: After initial repeated OVA exposure, mice were subjected to a protocol of antigen-induced airway inflammation, encompassing two intraperitoneal injections of OVA adsorbed to aluminium hydroxide followed by airway challenge. We assessed immune events in the draining lymph nodes after sensitization, and in the lungs after challenge. RESULTS: In animals initially exposed to OVA, we observed, at the time of sensitization, considerable expansion of T cells, many of which expressed the activation markers CD69 and CD25, as well as increased numbers of antigen-presenting cells, particularly B cells. While these animals produced low levels of IgE, the observed elevated levels of IgG1 signified isotype switching. Splenocytes and lymph node cells from OVA-exposed mice produced low levels of IL-4, IL-5, IL-13 and IFN-gamma, indicating aborted effector function of both T helper (Th)2- and Th1-associated cytokines. Real time quantitative polymerase chain reaction (PCR) (TaqMan) analysis of costimulatory molecules in the lungs after in vivo challenge showed that B7.1, B7.2, CD28 and CTLA-4 mRNA expression was low in animals initially exposed to OVA. Ultimately, these events were associated with abrogated airway inflammation and attenuated airway hyper-responsiveness. The decreased inflammation was antigen-specific and independent of IL-10 or IFN-gamma. CONCLUSION: Initial exposure to OVA establishes a programme that prevents the generation of intact, fully functional inflammatory responses upon secondary antigen encounter. The absence of inflammation, however, is not associated with categorical immune unresponsiveness.


Subject(s)
Cytokines/drug effects , Cytokines/immunology , Immunoglobulins/drug effects , Immunoglobulins/immunology , Inhalation Exposure/adverse effects , Mice, Inbred BALB C/immunology , Ovalbumin/immunology , Ovalbumin/pharmacology , Animals , Antibody Specificity/drug effects , Antibody Specificity/immunology , Biomarkers/blood , Bronchial Provocation Tests , Bronchoalveolar Lavage Fluid/chemistry , Bronchoalveolar Lavage Fluid/immunology , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Cytokines/blood , Dose-Response Relationship, Immunologic , Female , Histocompatibility Antigens Class II/drug effects , Histocompatibility Antigens Class II/immunology , Immunoglobulins/blood , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/metabolism , Lung/blood supply , Lung/cytology , Mice , Mice, Knockout , Models, Animal , RNA, Messenger/biosynthesis , RNA, Messenger/drug effects , Sodium Chloride/pharmacology , Time Factors
5.
Am J Respir Cell Mol Biol ; 25(3): 326-34, 2001 Sep.
Article in English | MEDLINE | ID: mdl-11588010

ABSTRACT

The objective of this study was to define phenotypic changes of antigen-presenting cells (APCs) and T cells in a murine model of antigen-induced airways inflammation that involves intraperitoneal sensitization with ovalbumin (OVA)/adjuvant followed by antigen aerosolization. We investigated the APC and T-cell compartments both after sensitization (primary immune response) and after challenge (secondary immune response) at the thoracic lymph nodes (initiation site) and the lung (effector site). Our findings document a major cellular expansion in the lymph nodes after both sensitization and challenge. After sensitization, this expansion was comprised mainly of B cells, a considerable proportion of which expressed B7.2. At this time, T cells were markedly expanded and activated as assessed by CD69 expression; further, although GATA-3 and signal transducer and activator of transcription-6 were expressed at this time point, expression of interleukin (IL)-4, IL-5, and IL-13 messenger RNA (mRNA) levels were marginal. However, in vitro stimulation of lymph-node cells with OVA led to cytokine production. In contrast, 24 h after challenge, but not after sensitization, there was a major expansion of dendritic cells and macrophages in the lungs. This expansion was associated with enhanced expression of both B7.1 and B7.2. We also observed expansion of activated CD3(+)/CD4(+) T cells expressing the T helper-2-associated marker T1/ST2 in the lung, most notably 5 d after challenge. Further, IL-4, IL-5, and IL-13, but not interferon-gamma mRNA were expressed at high levels 3 h after challenge. This study helps to elucidate the "geography" of immune responses generated in a conventional murine model of allergic airways inflammation.


Subject(s)
Antigen-Presenting Cells/immunology , Membrane Proteins , Ovalbumin/immunology , Pneumonia/immunology , T-Lymphocyte Subsets/immunology , Aerosols , Animals , Antigen-Presenting Cells/cytology , Antigen-Presenting Cells/metabolism , Antigens, CD/metabolism , B7-1 Antigen/metabolism , B7-2 Antigen , Bronchial Provocation Tests , Cytokines/genetics , Cytokines/metabolism , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Disease Models, Animal , Female , Flow Cytometry , GATA3 Transcription Factor , Histocompatibility Antigens Class II/metabolism , Interleukin-1 Receptor-Like 1 Protein , Lung/cytology , Lymph Nodes/cytology , Membrane Glycoproteins/metabolism , Mice , Mice, Inbred BALB C , Ovalbumin/administration & dosage , Pneumonia/chemically induced , Proteins/genetics , Proteins/metabolism , Receptors, Interleukin , STAT6 Transcription Factor , T-Lymphocyte Subsets/metabolism , Trans-Activators/genetics , Trans-Activators/metabolism
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