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Query: UMLS:C0009450 (infectious diseases)
 83,438 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Persistent viral infections continue to present major public health problems. Failure to achieve virus control confronts the immune system with a chronic viral burden that may involve immune cells themselves and directly compromise the functionality of effector lymphocytes and APCs. In this study we use the lymphocytic choriomeningitis virus system for persistent viral infection of its natural murine host and use analytical techniques for direct ex vivo visualization of virus-infected immune cells. We report that virtually all cells of the immune system can be infected, but the distribution of the viral burden is differentially allocated to lymphocyte and APC subsets of defined phenotypes. Importantly, the profile of immune cell infection found in the blood is broadly representative for the pattern of cellular infection in most organs and is independent of the presence of Abs or complement. By direct comparison of virus-infected and uninfected cell subsets, we demonstrate that lymphocytic choriomeningitis virus-infected T cells show preferential activation, skewed cytokine profiles, and increased apoptosis. In contrast, increased activation of APCs is generalized and independent of the presence of viral Ag. Our data indicate that specific patterns of immune cell infection are associated with distinct forms of immunostimulatory and immunosuppressive alterations that may provide insights into autoimmune processes associated with infectious disease and offer clues for therapeutic interventions aimed at restoration of complete immunity.
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PMID:Visualizing the viral burden: phenotypic and functional alterations of T cells and APCs during persistent infection. 1512 12

Although vaccines have been highly successful in preventing and treating many infectious diseases (including smallpox, polio and diphtheria) diseases prevalent in the developing world such as malaria and HIV, that suppress the host immune system, require new, multiple strategies that will be defined by our growing understanding of specific immune activation. The definition of adjuvants, previously thought of as any substance that enhanced the immunogenicity of antigen, could now include soluble mediators and antigenic carriers that interact with surface molecules present on DC (e.g. LPS, Flt3L, heat shock protein) particulate antigens which are taken up by mechanisms available to APC but not other cell types (e.g. immunostimulatory complexes, latex, polystyrene particles) and viral/bacterial vectors that infect antigen presenting cells (e.g. vaccinia, lentivirus, adenovirus). These approaches, summarized herein, have shown potential in vaccinating against disease in animal models, and in some cases in humans. Of these, particle-antigen conjugates provide rapid formulation of the vaccine, easy storage and wide application, with both carrier and adjuvant functions that activate DC. Combined vaccines of the future could use adjuvants such as virus-like particles and particles targeted towards a predominant cellular type or immune response, with target cell activation enhanced by growth factors or maturation signals prior to, or during immunization. Collectively, these new additions to adjuvant technology provide opportunities for more specific immune regulation than previously available.
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PMID:Vaccines that facilitate antigen entry into dendritic cells. 1547 36

Chickenpox is a common infectious disease of the pediatric age group with rare complications such as hemorrhagic varicella and arterial thrombotic purpura. Medical support is the mainstay of treatment in such cases but for the rescue of necrotic tissues, hyperbaric oxygen (HBO) therapy should be applied in addition to anticoagulant intervention. We report an infant with acute arterial thrombotic purpura which developed after varicella eruption and who made full recovery with the help of HBO as an adjunctive treatment modality. Fresh frozen plasma and low molecular weight heparin were given for prolonged prothrombin time and thromboemboli on the 2nd-4th digits of his right foot. Protein C, protein S and factor V levels were found to be normal in our patient. Necrotic lesions on the toes regressed with repeated HBO treatment and amputation was not needed.
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PMID:Acute arterial thrombotic purpura complicating varicella and the role of hyperbaric oxygen as an adjunctive therapy. 1550 80

APC are used extensively to induce and expand Ag-specific T cells as well as to test their specificity and function. In the treatment of malignant and infectious diseases, APC are used to stimulate and expand Ag-specific T cells for adoptive transfer, or used directly in vivo to present Ag. The choice of APC to use depends on the particular application and on practical considerations, which include ease of production, availability, reproducibility and (for clinical use) established safety. The diversity of APC in use partly reflects the fact that no single technique of Ag presentation is ideal. For the clinician and laboratory worker alike the field can seem illogical and confusing. In this review we outline the functional requirements of APC for the induction of T cells, classify the APC in common use and describe their laboratory and clinical applications.
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PMID:An APC for every occasion: induction and expansion of human Ag-specific CD4 and CD8 T cells using cellular and non-cellular APC. 1551 10

IFN-alphabeta functions in the transition from innate to adaptive immunity and may impinge on the interaction of Mycobacterium tuberculosis with its host. Infection by M. tuberculosis causes IFN-alphabeta secretion and down-regulation of IFN-alphabeta signaling in human APC and the human monocytic cell line THP-1, which provides a model for these studies. Neutralization of secreted IFN-alphabeta prevents inhibition of IFN-alpha signaling during infection, but several lines of evidence distinguish inhibition due to infection from a negative feedback response to only IFN-alphabeta. First, greater inhibition of IFN-alpha-stimulated STAT-1 tyrosine phosphorylation occurs 3 days postinfection than 1 or 3 days after IFN-alphabeta pretreatment. Second, LPS also induces IFN-alphabeta secretion and causes IFN-alphabeta-dependent down-regulation of IFN-alpha signaling, yet the inhibition differs from that caused by infection. Third, IFN-alpha signaling is inhibited when cells are grown in conditioned medium collected from infected cells 1 day postinfection, but not if it is collected 3 days postinfection. Because IFN-alphabeta is stable, the results with conditioned medium suggest the involvement of an additional, labile substance during infection. Further characterizing signaling for effects of infection, we found that cell surface IFN-alphabeta receptor is not reduced by infection, but that infection increases association of protein tyrosine phosphatase 1c with the receptor and with tyrosine kinase 2. Concomitantly, IFN-alpha stimulation of tyrosine kinase 2 tyrosine phosphorylation and kinase activity decreases in infected cells. Moreover, infection reduces the abundance of JAK-1 and tyrosine-phosphorylated JAK-1. Thus, the distinctive down-regulation of IFN-alpha signaling by M. tuberculosis occurs together with a previously undescribed combination of inhibitory intracellular events.
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PMID:IFN-alpha beta secreted during infection is necessary but not sufficient for negative feedback regulation of IFN-alpha beta signaling by Mycobacterium tuberculosis. 1563 24

Infection with the human immunodeficiency virus (HIV) is still a major health problem world-wide. HIV infection has changed into a chronic infection with the chance of developing long-term complications. Vascular complications are frequently reported in the current literature. HIV and treatment by highly active antiretroviral therapy (HAART) are associated with many cardiovascular risk factors. An increased risk of arterial cardiovascular complications was found in a number of studies. However, data about the risk of venous thrombotic disease (VTE), including potentially fatal conditions as pulmonary embolism, were limited. In a systematic review of the literature, ten relevant epidemiological studies were identified that investigated the risk of venous thrombotic disease in HIV-infected patients. The incidence was increased two- to tenfold in comparison with a healthy population of the same age. However, these studies were mainly retrospective cohort studies that were prone to selection bias, confounding factors were not always mentioned and in all but three control populations were missing. An increased risk of venous thrombotic disease in HIV-infected patients could be explained by the presence of a hypercoagulable state, characterised by an increase in procoagulant factors, such as endothelial TF expression and thrombogenic properties of microparticles, and a decrease in anticoagulant factors, including AT III, HC II and the protein C pathway. Furthermore, the risk of VTE was associated with an increased risk of infections and autoimmune haemolytic anaemia, and was weakly associated with HAART. All together, quite some evidence pointed towards a relationship between HIV infection and venous thrombotic disease, but the association still needs to be established in properly designed epidemiological studies.
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PMID:Is chronic HIV infection associated with venous thrombotic disease? A systematic review. 1586 40

Cell-mediated immunity and production of type 1 cytokines are the main defenses against pathogenic fungi. Ligation of CD40 by CD40L on T cells is critical for the induction of these immune responses in vivo. We explored the role of CD40/CD40L interactions in vaccine immunity to Blastomyces dermatitidis by immunizing CD40(-/-) and CD40L(-/-) mice and analyzing their resistance to reinfection in a murine pulmonary model. In the absence of CD40 or CD40L, CD4(+) cells failed to get primed or produce type 1 cytokine and impaired the generation of CD8(+) T1 cells. The CD8(+) T cell defect was not due to regulatory T cells or impaired APC maturation or Ag presentation to T cells. If CD4(+) cells were first eliminated, vaccination of CD40(-/-) and CD40L(-/-) mice restored priming of CD8(+) cells, type 1 cytokine production, and resistance. Hence, CD4(+) and CD8(+) cells differ sharply in their requirement for CD40/CD40L interaction during the generation of antifungal immunity. Despite the plasticity of T cell subsets in vaccine immunity, in absence of CD40/CD40L interaction, CD4(+) cells may impede the priming of CD8(+) cells at the cost of host survival against a lethal infectious disease.
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PMID:Differential requirements of T cell subsets for CD40 costimulation in immunity to Blastomyces dermatitidis. 1662 23

The ex vivo priming and expansion of human CTL by APC, such as autologous monocyte-derived dendritic cells (DC), has the potential for use in immunotherapy for infectious diseases and cancer. To overcome the difficulty of obtaining sufficient number of autologous DC from patients, we have developed cell-based artificial APC (aAPC), designated Med-APC. These aAPC rapidly activate and expand the corresponding Ag-specific CD8+ T cells when pulsed with CTL epitope peptide(s) as efficiently as mature DC (mDC). We have also shown that Med-APC possess an innate cellular machinery that is sufficient to support the processing of complete Ag into immunodominant peptides, which considerably extends the usefulness of this technology. In addition, we have developed a novel expression vector system that expresses ubiquitinated Ag, resulting in an enhanced APC function of this system. Genetically encoded Ag can be easily introduced into Med-APC by transfection with this vector. Med-APC transfected with ubiquitinated Ag can efficiently expand the corresponding Ag-specific CTL without exogenous peptides. Therefore, Med-APC may have important therapeutic implications for adoptive immunotherapy and can be used for the detection of Ag-specific CTL for immunomonitoring.
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PMID:Efficient priming and expansion of antigen-specific CD8+ T cells by a novel cell-based artificial APC. 1686 38

The use of particulate carriers holds great promise for the development of effective and affordable recombinant vaccines. Rational development requires a detailed understanding of particle up-take and processing mechanisms to target cellular pathways capable of stimulating the required immune responses safely. These mechanisms are in turn based on how the host has evolved to recognize and process pathogens. Pathogens, as well as particulate vaccines, come in a wide range of sizes and biochemical compositions. Some of these also provide 'danger signals' so that antigen 'senting cells (APC), usually dendritic cells (DC), acquire specific stimulatory activity. Herein, we provide an overview of the types of particles currently under investigation for the formulation of vaccines, discuss cellular uptake mechanisms (endocytosis, macropinocytosis, phagocytosis, clathrin-dependent and/or caveloae-mediated) for pathogens and particles of different sizes, as well as antigen possessing and presentation by APC in general, and DC in particular. Since particle size and composition can influence the immune response, inducing humoral and/or cellular immunity, activating CD8 T cells and/or CD4 T cells of T helper 1 and/or T helper 2 type, particle characteristics have a major impact on vaccine efficacy. Recently developed methods for the formulation of particulate vaccines are presented in this issue of Methods, showcasing a range of "cutting edge" particulate vaccines that employ particles ranging from nano to micro-sized. This special issue of Methods further addresses practical issues of production, affordability, reproducibility and stability of formulation, and also includes a discussion of the economic and regulatory challenges encountered in developing vaccines for veterinary use and for common Third World infectious diseases.
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PMID:Pathogen recognition and development of particulate vaccines: does size matter? 1699 8

The development of new, effective, easy-to-use and lower-cost vaccination approaches for the combat against malignant and infectious diseases is a pre-eminent need: cancer is a leading cause of morbidity in the Western World; there are numerous pathogenic diseases for which we still have no protective or therapeutic cure; and the financial limitations of developing countries to fight these diseases. In this mini-review we focus on transcutaneous immunization (TCI), a relatively new route for antigen delivery. TCI protocols appear to be particularly promising by gaining access to skin resident APC, which are highly efficient for the initiation of humoral and/or cellular immune responses. Consisting of an adjuvant as a stimulus in combination with an antigen which defines the target, TCI offers a most attractive immunization strategy to mount highly specific full-blown adaptive immune responses. As a topically applicable cell-free adjuvant/antigen mixture, TCI might be suitable to improve patient compliance, as well as feasible economically for the use in Third World countries. In addition, this non-invasive procedure might increase the safety of vaccinations by eliminating the risk of infections related to the recycling and improper disposal of needles. The dissection of antigen and adjuvant is important because it allows "free" combinations in contrast to classical immunizations which are based on application of the pathogen of interest. The most relevant ways and means to find new, effective pathogenic target antigens are "reverse vaccinology" and the direct peptide-epitope identification from MHC molecules with mass-spectrometry. Due to these efficient approaches the variety of antigenic epitopes for potential protective/therapeutic use is perpetually expanding. The most studied adjuvants in TCI approaches are cholera toxin (CT) and its less toxic relative, the heat-labile enterotoxin (LT). Both CT and LT can serve as antigen as well. In contrast to these large proteins, which can only penetrate "pre-treated" skin barrier, the immune response modifier, TLR7 agonist R-837 (Imiquimod) is a small compound adjuvant that easily passages non-disrupted epidermis. It remains currently elusive which cells of the complex-structured "skin-associated lymphoid tissue" (SALT) respond to the adjuvant and which APC carries the antigen to the draining lymphnodes for subsequent initiation of adaptive immune responses.
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PMID:Initiation of adaptive immune responses by transcutaneous immunization. 1732 Jan 94


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