Mucosally delivered dendritic cells activate T cells independently of IL-12 and endogenous APCs.

In vitro manipulated dendritic cells (DC) have increasingly been used as a promising vaccine formulation against cancer and infectious disease. However, improved understanding of the immune mechanisms is needed for the development of safe and efficacious mucosal DC immunization. We have developed a murine model of respiratory mucosal immunization by using a genetically manipulated DC vaccine.

In vivo-to-in silico iterations to investigate aeroallergen-host interactions.

Background: Allergic asthma is a complex process arising out of the interaction between the immune system and aeroallergens. Yet, the relationship between aeroallergen exposure, allergic sensitization and disease remains unclear. This knowledge is essential to gain further insight into the origin and evolution of allergic diseases.

Impact of cigarette smoke on T and B cell responsiveness.

Although its direct effects cannot be discounted, tobacco's effects on the immune system have been proposed to play a key role in mediating its deleterious health impact. Studies in rats using high levels of smoke exposure have suggested that tobacco smoke exhausts cellular signal transduction cascades, making lymphocytes unresponsive to stimulation. In the present study, we show that purified B or T cells, and total lymphocytes from the lungs, lymph nodes and spleens of smoke-exposed mice fluxed calcium, proliferated, and secreted immunoglobulin or IFN-gamma similarly to control mice when stimulated with ligands including anti-IgM, and anti-CD3.

Heterologous boosting of recombinant adenoviral prime immunization with a novel vesicular stomatitis virus-vectored tuberculosis vaccine.

Pulmonary tuberculosis (TB) remains a serious health problem worldwide. Effective vaccination strategies are needed. We report the development of a novel TB vaccine using vesicular stomatitis virus (VSV) as a viral vector system to express Ag85A.

Cigarette smoke suppresses type I interferon-mediated antiviral immunity in lung fibroblast and epithelial cells.

The objective of this study was to investigate the impact of cigarette smoke on innate antiviral defense mechanisms; specifically, we examined the effects of cigarette smoke on the induction of type I interferon (IFN). We observed a dose-dependent decrease in the ability of human lung fibroblast and epithelial cells to elicit an antiviral response against a viral double-strand RNA (dsRNA) mimic, polyI:C, in the presence of cigarette smoke-conditioned medium (SCM). Mechanistically, SCM decreases the expression of IFN-stimulated gene 15 (ISG15) and IFN regulatory factor-7 (IRF-7) transcripts and suppresses the nuclear translocation of key transcription factors, nuclear factor-kappaB (NF-kappaB) and IRF-3, after polyI:C stimulation.

Organ distribution of transgene expression following intranasal mucosal delivery of recombinant replication-defective adenovirus gene transfer vector.

It is believed that respiratory mucosal immunization triggers more effective immune protection than parenteral immunization against respiratory infection caused by viruses and intracellular bacteria. Such understanding has led to the successful implementation of intranasal immunization in humans with a live cold-adapted flu virus vaccine. Furthermore there has been an interest in developing effective mucosal-deliverable genetic vaccines against other infectious diseases.

Inflammation and the aging process: devil or angel.

Inflammation is often viewed as a pathologic mechanism leading to tissue damage and interference with function, such as the process of chronic tissue scarring or fibrosis. However, it is important to note that inflammation is a crucial component of normal tissue repair as well as being fundamental to the body's defense against infection. Considering inflammation as a "causative agent in aging" belies the underlying mechanisms whereby the acute inflammatory response is necessary for survival, and efforts to reduce and control the inflammatory response leave the host susceptible to infectious agents and improper healing.

Impact of CD40 ligand, B cells, and mast cells in peanut-induced anaphylactic responses.

The effector immune mechanisms underlying peanut-induced anaphylaxis remain to be fully elucidated. We investigated the relative contribution of Igs, mast cells (MCs), and FcepsilonRI in the elicitation of anaphylaxis in a murine model. Assessment of peanut hypersensitivity reactions was performed clinically and biologically.

Critical negative regulation of type 1 T cell immunity and immunopathology by signaling adaptor DAP12 during intracellular infection.

Transmembrane signaling adaptor DAP12 has increasingly been recognized for its important role in innate responses. However, its role in the regulation of antimicrobial T cell responses has remained unknown. In our current study, we have examined host defense, T cell responses, and tissue immunopathology in models of intracellular infection established in wild-type and DAP12-deficient mice.

Th2 differentiation in distinct lymph nodes influences the site of mucosal Th2 immune-inflammatory responses.

Allergic individuals rarely present with concurrent multiple-organ disease but, rather, with manifestations that privilege a specific site such as the lung, skin, or gastrointestinal tract. Whether the site of allergic sensitization influences the localization of Th2 immune-inflammatory responses and, ultimately, the organ-specific expression of disease, remains to be determined. In this study, we investigated whether both the site of initial Ag exposure and concomitant Th2 differentiation in specific lymph nodes (LNs) privileges Th2 memory responses to mucosal and nonmucosal sites, and whether this restriction is associated with a differential expression in tissue-specific homing molecules.

Animal models of chronic obstructive pulmonary disease exacerbations.

Modeling acute exacerbations of chronic obstructive pulmonary disease (AECOPD) in animals has proven challenging due to the clinical and pathological complexity of the underlying disease. This has hindered the progress in understanding the cellular and molecular mechanisms that lie beneath AECOPD. In this chapter, we will address modeling possibilities of AECOPD that may be drawn from the current knowledge of factors that cause exacerbations.

Modeling responses to respiratory house dust mite exposure.

House dust mite (HDM) is the most pervasive indoor aeroallergen source worldwide. Allergens derived from HDM are associated with sensitization and allergic asthma. Allergic asthma is an immunologically driven disease characterized by a Th2-polarized immune response, eosinophilic inflammation, airway hyperreactivity, and remodeling.

Heterologous boost vaccines for bacillus Calmette-Guérin prime immunization against tuberculosis.

The current tuberculosis (TB) epidemic continues to call for the development of effective vaccination strategies. The initial TB vaccine research effort mostly focused on the search for a vaccine that might be better than, and thus could replace, the current bacillus Calmette-Guérin (BCG) vaccine. It has increasingly been realized that BCG or an improved BCG will continue to be used as a prime TB vaccine and there is a need to develop effective boost vaccines that could enhance and prolong the protective immunity of BCG prime immunization.

Adaptive immune responses fail to provide protection against genital HSV-2 infection in the absence of IL-15.

IL-15 plays a crucial role in innate defense against viral infections. The role of IL-15 in the generation and function of adaptive immunity, following mucosal immunization, against genital HSV-2 has not been studied. Here, we report that immunized IL-15(-/-) mice were able to generate antibody and T cell-mediated immune responses against HSV-2, comparable to those seen in immunized B6 mice.

Divergent immune responses to house dust mite lead to distinct structural-functional phenotypes.

Asthma is a chronic airway inflammatory disease that encompasses three cardinal processes: T helper (Th) cell type 2 (Th2)-polarized inflammation, bronchial hyperreactivity, and airway wall remodeling. However, the link between the immune-inflammatory phenotype and the structural-functional phenotype remains to be fully defined. The objective of these studies was to evaluate the relationship between the immunologic nature of chronic airway inflammation and the development of abnormal airway structure and function in a mouse model of chronic asthma.

Expression of Toll-like receptors in murine vaginal epithelium is affected by the estrous cycle and stromal cells.

Vaginal epithelium is regulated by female sex hormones and serves as the first line of innate immune defense against sexually transmitted infections (STIs). This occurs in part through recognition of pathogens via Toll-like receptors (TLRs); however, the expression and role of TLRs in reproductive tract immunity are poorly understood. Here, we have compared the effect of the estrous cycle and treatment with DepoProvera (Depo) on TLR mRNA expression in whole mouse vaginal tissue, vaginal epithelium isolated using laser capture microdissection (LCM) and in primary vaginal epithelial cells (ECs) grown in vitro.

Immunoreactivity profile of peripheral blood mononuclear cells from patients with ragweed-induced allergic rhinitis.

Background: Seasonal rhinitis is manifested by a series of nasal symptoms in response to exposure to seasonal allergens including ragweed pollen. Understanding its immunological mechanisms may help to better manage the disease.

Objective: We sought to determine comprehensively ragweed-induced cytokine and chemokine production by peripheral blood mononuclear cells from normal individuals and patients with seasonal rhinitis sensitized to ragweed pollen, and to assess its regulation by exogenous IL-10.

Adenoviral gene transfer of bioactive TGFbeta1 to the rodent eye as a novel model for anterior subcapsular cataract.

Purpose: To produce a gene-transfer model of rodent anterior subcapsular cataracts (ASC) using a replication-deficient, adenoviral vector containing active TGFbeta1. Establishment of this model will be important for further investigations of TGFbeta-induced signaling cascades in ASC.

Methods: Adenovirus containing the transgene for active TGFbeta1 (AdTGFbeta1), beta-galactosidase (AdLacZ), green fluorescent protein (AdGFP) or no transgene (AdDL) was injected into the anterior chamber of C57Bl/6, Smad3 WT and Smad3 KO mice.

Cigarette smoke impairs NK cell-dependent tumor immune surveillance.

In this study, we investigated the impact of cigarette smoke on tumor immune surveillance and its consequences to lung tumor burden in a murine lung metastasis model. Cigarette smoke exposure significantly increased the numbers of lung metastases following B16-MO5 melanoma challenge. This effect was reversible; we observed significantly fewer tumor nodules following smoking cessation.

Oncostatin M-induced IL-6 expression in murine fibroblasts requires the activation of protein kinase Cdelta.

Oncostatin M (OSM) is an IL-6/LIF cytokine family member whose role has been identified in a range of biological activities in vitro, including up-regulation of inflammatory gene expression and regulation of connective tissue metabolism. However, the mechanisms through which OSM regulates cellular responses are not completely understood. In this study, we show that activation of the calcium-independent or novel protein kinase C (PKC) isoform PKCdelta is a critical event during OSM-mediated up-regulation of IL-6 expression in murine fibroblasts.

The direct effects of Toll-like receptor ligands on human NK cell cytokine production and cytotoxicity.

Toll-like receptor (TLR) ligands are potent inducers of the innate immune system, of which NK and NKT cells play an important role. We examined the direct activation of highly purified human NK and/or NKT cells with known TLR ligands. NK/NKT cells were positive for all known TLR mRNA (TLR1-10).

Matrix protein of Vesicular stomatitis virus harbours a cryptic mitochondrial-targeting motif.

Vesicular stomatitis virus (VSV) is a rhabdovirus that has attracted attention of late as an oncolytic virus and as a vaccine vector. Mutations in the matrix (M) gene of VSV yield attenuated strains that may be very useful in both settings. As a result of this interest in the M protein, this study analysed various M-green fluorescent protein (GFP) fusion constructs.

Cigarette smoke impacts immune inflammatory responses to influenza in mice.

Rationale: Studies have shown that cigarette smoke impacts respiratory host defense mechanisms; however, it is poorly understood how these smoke-induced changes impact the overall ability of the host to deal with pathogenic agents.

Objective: The objective of this study was to investigate the impact of mainstream cigarette smoke exposure on immune inflammatory responses and viral burden after respiratory infection with influenza A.

Methods: C57BL/6 mice were sham- or smoke-exposed for 3 to 5 mo and infected with either 2.

Induction of innate immunity against herpes simplex virus type 2 infection via local delivery of Toll-like receptor ligands correlates with beta interferon production.

Toll-like receptors (TLRs) constitute a family of innate receptors that recognize and respond to a wide spectrum of microorganisms, including fungi, bacteria, viruses, and protozoa. Previous studies have demonstrated that ligands for TLR3 and TLR9 induce potent innate antiviral responses against herpes simplex virus type 2 (HSV-2). However, the factor(s) involved in this innate protection is not well-defined.